[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Emerging insights into pulmonary hypertension: the potential role of mitochondrial dysfunction and redox homeostasis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Pulmonary hypertension (PH) is heterogeneous diseases that can lead to death due to progressive right heart failure. Emerging evidence suggests that, in addition to its role in ATP production, changes in mitochondrial play a central role in their pathogenesis, regulating integrated metabolic and signal transduction pathways. This review focuses on the basic principles of mitochondrial redox status in pulmonary vascular and right ventricular disorders, a series of dysfunctional processes including mitochondrial quality control (mitochondrial biogenesis, mitophagy, mitochondrial dynamics, mitochondrial unfolded protein response) and mitochondrial redox homeostasis. In addition, we will summarize how mitochondrial renewal and dynamic changes provide innovative insights for studying and evaluating PH. This will provide us with a clearer understanding of the initial signal transmission of mitochondria in PH, which would further improve our understanding of the pathogenesis of PH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

No datasets were generated or analysed during the current study.

References

  1. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01913-2018

    Article  PubMed  PubMed Central  Google Scholar 

  2. Chan SY, Loscalzo J (2008) Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol 44:14–30. https://doi.org/10.1016/j.yjmcc.2007.09.006

    Article  CAS  PubMed  Google Scholar 

  3. Farber HW, Miller DP, Poms AD, Badesch DB, Frost AE, Muros-Le Rouzic E, Romero AJ, Benton WW, Elliott CG, McGoon MD, Benza RL (2015) Five-year outcomes of patients enrolled in the REVEAL registry. Chest 148:1043–1054. https://doi.org/10.1378/chest.15-0300

    Article  PubMed  Google Scholar 

  4. Protasoni M, Zeviani M (2021) Mitochondrial structure and bioenergetics in normal and disease conditions. Int J Mol Sci. https://doi.org/10.3390/ijms22020586

    Article  PubMed  PubMed Central  Google Scholar 

  5. Geng Y, Hu Y, Zhang F, Tuo Y, Ge R, Bai Z (2023) Mitochondria in hypoxic pulmonary hypertension, roles and the potential targets. Front Physiol 14:1239643. https://doi.org/10.3389/fphys.2023.1239643

    Article  PubMed  PubMed Central  Google Scholar 

  6. Anso E, Weinberg SE, Diebold LP, Thompson BJ, Malinge S, Schumacker PT, Liu X, Zhang Y, Shao Z, Steadman M, Marsh KM, Xu J, Crispino JD, Chandel NS (2017) The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat Cell Biol 19:614. https://doi.org/10.1038/ncb3529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chang X, Zhang W, Zhao Z, Ma C, Zhang T, Meng Q, Yan P, Zhang L, Zhao Y (2020) Regulation of mitochondrial quality control by natural drugs in the treatment of cardiovascular diseases: potential and advantages. Front Cell Dev Biol. https://doi.org/10.3389/fcell.2020.616139

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zorov DB, Juhaszova M, Sollott SJ (2006) Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta 1757:509–517. https://doi.org/10.1016/j.bbabio.2006.04.029

    Article  CAS  PubMed  Google Scholar 

  9. Adesina SE, Kang B-Y, Bijli KM, Ma J, Cheng J, Murphy TC, Hart CM, Sutliff RL (2015) Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radical Biol Med 87:36–47. https://doi.org/10.1016/j.freeradbiomed.2015.05.042

    Article  CAS  Google Scholar 

  10. Pak O, Sommer N, Hoeres T, Bakr A, Waisbrod S, Sydykov A, Haag D, Esfandiary A, Kojonazarov B, Veit F, Fuchs B, Weisel FC, Hecker M, Schermuly RT, Grimminger F, Ghofrani HA, Seeger W, Weissmann N (2013) Mitochondrial hyperpolarization in pulmonary vascular remodeling mitochondrial uncoupling protein deficiency as disease model. Am J Respir Cell Mol Biol 49:358–367. https://doi.org/10.1165/rcmb.2012-0361OC

    Article  CAS  PubMed  Google Scholar 

  11. Diebold I, Hennigs JK, Miyagawa K, Li CG, Nickel NP, Kaschwich M, Cao A, Wang L, Reddy S, Chen P-I, Nakahira K, Alcazar MAA, Hopper RK, Ji L, Feldman BJ, Rabinovitch M (2015) BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell Metab 21:596–608. https://doi.org/10.1016/j.cmet.2015.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Afolayan AJ, Eis A, Alexander M, Michalkiewicz T, Teng R-J, Lakshminrusimha S, Konduri GG (2016) Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension. Am J Phys Lung Cell Mol Phys 310:L40–L49. https://doi.org/10.1152/ajplung.00392.2014

    Article  Google Scholar 

  13. Zhang W, Liu B, Wang Y, Zhang H, He L, Wang P, Dong M (2022) Mitochondrial dysfunction in pulmonary arterial hypertension. Front Physiol 13:1079989. https://doi.org/10.3389/fphys.2022.1079989

    Article  PubMed  PubMed Central  Google Scholar 

  14. Suliman HB, Nozik-Grayck E (2019) Mitochondrial dysfunction: metabolic drivers of pulmonary hypertension. Antioxid Redox Signal 31:843–857. https://doi.org/10.1089/ars.2018.7705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Colon Hidalgo D, Elajaili H, Suliman H, George MP, Delaney C, Nozik E (2022) Metabolism, mitochondrial dysfunction, and redox homeostasis in pulmonary hypertension. Antioxidants (Basel). https://doi.org/10.3390/antiox11020428

    Article  PubMed  Google Scholar 

  16. Ryanto GRT, Suraya R, Nagano T (2023) Mitochondrial dysfunction in pulmonary hypertension. Antioxidants (Basel). https://doi.org/10.3390/antiox12020372

    Article  PubMed  Google Scholar 

  17. Pokharel MD, Marciano DP, Fu P, Franco MC, Unwalla H, Tieu K, Fineman JR, Wang T, Black SM (2023) Metabolic reprogramming, oxidative stress, and pulmonary hypertension. Redox Biol 64:102797. https://doi.org/10.1016/j.redox.2023.102797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Piantadosi CA, Suliman HB (2017) Mitochondrial dysfunction in lung pathogenesis. Annu Rev Physiol 79:495–515

    Article  CAS  PubMed  Google Scholar 

  19. Dupre TV, Jenkins DP, Muise-Helmericks RC, Schnellmann RG (2019) The 5-hydroxytryptamine receptor 1F stimulates mitochondrial biogenesis and angiogenesis in endothelial cells. Biochem Pharm. https://doi.org/10.1016/j.bcp.2019.113644

    Article  PubMed  Google Scholar 

  20. Rehman J, Archer SL (2010) A Proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the warburg model of pulmonary arterial hypertension. In: Yuan JXJ, Ward JPT (eds) Membrane receptors, channels and transporters in pulmonary circulation. Humana Press, Totowa, pp 171–185

    Chapter  Google Scholar 

  21. Hock MB, Kralli A (2009) Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol 71:177–203. https://doi.org/10.1146/annurev.physiol.010908.163119

    Article  CAS  PubMed  Google Scholar 

  22. Hu X, Xu X, Lu Z, Zhang P, Fassett J, Zhang Y, Xin Y, Hall JL, Viollet B, Bache RJ, Huang Y, Chen Y (2011) AMP activated protein kinase-alpha 2 regulates expression of estrogen-related receptor-alpha, a metabolic transcription factor related to heart failure development. Hypertension 58:696-U376. https://doi.org/10.1161/hypertensionaha.111.174128

    Article  CAS  PubMed  Google Scholar 

  23. Yeligar SM, Kang BY, Bijli KM, Kleinhenz JM, Murphy TC, Torres G, San Martin A, Sutliff RL, Hart CM (2018) PPARγ regulates mitochondrial structure and function and human pulmonary artery smooth muscle cell proliferation. Am J Respir Cell Mol Biol 58:648–657. https://doi.org/10.1165/rcmb.2016-0293OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Abdulkareem AO, Tiwari P, Lone ZR, Iqbal H, Gupta S, Jha RK, Chanda D, Jagavelu K, Hanif K (2023) Ormeloxifene, a selective estrogen receptor modulator, protects against pulmonary hypertension. Eur J Pharmacol 943:175558. https://doi.org/10.1016/j.ejphar.2023.175558

    Article  CAS  PubMed  Google Scholar 

  25. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 19:557–566. https://doi.org/10.1038/nm.3159

    Article  CAS  PubMed  Google Scholar 

  26. Hondares E, Mora O, Yubero P, Rodriguez de la Concepcion M, Iglesias R, Giralt M, Villarroya F (2006) Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-1 alpha gene transcription: an autoregulatory loop controls PGC-1 alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation. Endocrinology 147:2829–2838. https://doi.org/10.1210/en.2006-0070

    Article  CAS  PubMed  Google Scholar 

  27. Dominy JE, Puigserver P (2013) Mitochondrial biogenesis through activation of nuclear signaling proteins. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a015008

    Article  PubMed  PubMed Central  Google Scholar 

  28. Scarpulla RC, Vega RB, Kelly DP (2012) Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab 23:459–466. https://doi.org/10.1016/j.tem.2012.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ding M, Lei J, Qu Y, Zhang H, Xin W, Ma F, Liu S, Li Z, Jin F, Fu E (2015) Calorie restriction attenuates monocrotaline-induced pulmonary arterial hypertension in rats. J Cardiovasc Pharmacol 65:562–570. https://doi.org/10.1097/fjc.0000000000000224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zurlo G, Piquereau J, Moulin M, Da Silva JP, Gressette M, Ranchoux B, Garnier A, Ventura-Clapier R, Fadel E, Humbert M, Lemaire C, Perros F, Veksler V (2018) Sirtuin 1 regulates pulmonary artery smooth muscle cell proliferation: role in pulmonary arterial hypertension. J Hypertens 36:1164–1177. https://doi.org/10.1097/hjh.0000000000001676

    Article  CAS  PubMed  Google Scholar 

  31. Rao J, Li J, Liu Y, Lu P, Sun X, Sugumaran PK, Zhu D (2012) The key role of PGC-1 alpha in mitochondrial biogenesis and the proliferation of pulmonary artery vascular smooth muscle cells at an early stage of hypoxic exposure. Mol Cell Biochem 367:9–18. https://doi.org/10.1007/s11010-012-1313-z

    Article  CAS  PubMed  Google Scholar 

  32. Mata M, Sarrion I, Milian L, Juan G, Ramon M, Naufal D, Gil J, Ridocci F, Fabregat-Andres O, Cortijo J (2012) PGC-1 alpha induction in pulmonary arterial hypertension. Oxid Med Cell Longev. https://doi.org/10.1155/2012/236572

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tielemans B, Delcroix M, Belge C, Quarck R (2019) TGF and BMPRII signalling pathways in the pathogenesis of pulmonary arterial hypertension. Drug Discovery Today 24:703–716. https://doi.org/10.1016/j.drudis.2018.12.001

    Article  CAS  PubMed  Google Scholar 

  34. Villeneuve C, Guilbeau-Frugier C, Sicard P, Lairez O, Ordener C, Duparc T, De Paulis D, Couderc B, Spreux-Varoquaux O, Tortosa F, Garnier A (2013) P53-PGC-1α pathway mediates oxidative mitochondrial damage and cardiomyocyte necrosis induced by monoamine oxidase-a upregulation: Role in chronic left ventricular dysfunction in mice. Antioxid Redox Signal 18(1):5–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski M, Barsh GS, Clayton DA (1998) Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet 18:231–236. https://doi.org/10.1038/ng0398-231

    Article  CAS  PubMed  Google Scholar 

  36. Mammoto A, Muyleart M, Kadlec A, Gutterman D, Mammoto T (2018) YAP1-TEAD1 signaling controls angiogenesis and mitochondrial biogenesis through PGC1α. Microvasc Res 119:73–83. https://doi.org/10.1016/j.mvr.2018.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Eisele PS, Salatino S, Sobek J, Hottiger MO, Handschin C (2013) The peroxisome proliferator-activated receptor gamma coactivator 1 alpha/beta (PGC-1) coactivators repress the transcriptional activity of NF-kappa B in skeletal muscle cells. J Biol Chem 288:2246–2260. https://doi.org/10.1074/jbc.M112.375253

    Article  CAS  PubMed  Google Scholar 

  38. Ramachandran A, Levonen AL, Brookes PS, Ceaser E, Shiva S, Barone MC, Darley-Usmar V (2002) Mitochondria, nitric oxide, and cardiovascular dysfunction. Free Radical Biol Med 33:1465–1474. https://doi.org/10.1016/s0891-5849(02)01142-5

    Article  CAS  Google Scholar 

  39. Forstermann U, Schmidt HH, Pollock JS, Sheng H, Mitchell JA, Warner TD, Nakane M, Murad F (1991) Isoforms of nitric oxide synthase. Characterization and purification from different cell types. Biochem Pharmacol 42:1849–1857. https://doi.org/10.1016/0006-2952(91)90581-o

    Article  CAS  PubMed  Google Scholar 

  40. Aggarwal S, Gross CM, Sharma S, Fineman JR, Black SM (2013) Reactive oxygen species in pulmonary vascular remodeling. Compr Physiol 3:1011–1034. https://doi.org/10.1002/cphy.c120024

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ye J-X, Wang S-S, Ge M, Wang D-J (2016) Suppression of endothelial PGC-1 alpha is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension. Am J Phys Lung Cell Mol Phys 310:L1233–L1242. https://doi.org/10.1152/ajplung.00356.2015

    Article  Google Scholar 

  42. Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C, Dweik RA, Tuder RM, Stuehr DJ, Erzurum SC (2007) Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci USA 104:1342–1347. https://doi.org/10.1073/pnas.0605080104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao Q, Zhang J, Wang H (2015) PGC-1α overexpression suppresses blood pressure elevation in DOCA-salt hypertensive mice. Biosci Rep. https://doi.org/10.1042/bsr20150076

  44. Rana U, Callan E, Entringer B, Michalkiewicz T, Joshi A, Parchur AK, Teng RJ, Konduri GG (2020) AMP-kinase dysfunction alters notch ligands to impair angiogenesis in neonatal pulmonary hypertension. Am J Respir Cell Mol Biol 62:719–731. https://doi.org/10.1165/rcmb.2019-0275OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li J, Zhang Y, Liu Y, Shen T, Zhang H, Xing Y, Zhu D (2015) PGC-1 alpha plays a major role in the anti-apoptotic effect of 15-HETE in pulmonary artery endothelial cells. Respir Physiol Neurobiol 205:84–91. https://doi.org/10.1016/j.resp.2014.10.015

    Article  CAS  PubMed  Google Scholar 

  46. Liu A, Philip J, Vinnakota KC, Van den Bergh F, Tabima DM, Hacker T, Beard DA, Chesler NC (2017) Estrogen maintains mitochondrial content and function in the right ventricle of rats with pulmonary hypertension. Physiol Rep. https://doi.org/10.14814/phy2.13157

    Article  PubMed  PubMed Central  Google Scholar 

  47. Spyropoulos F, Michael Z, Finander B, Vitali S, Kosmas K, Zymaris P, Kalish BT, Kourembanas S, Christou H (2021) Acetazolamide improves right ventricular function and metabolic gene dysregulation in experimental pulmonary arterial hypertension. Front Cardiovasc Med. https://doi.org/10.3389/fcvm.2021.662870

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kobayashi T, Kim JD, Naito A, Yanagisawa A, Jujo-Sanada T, Kasuya Y, Nakagawa Y, Sakao S, Tatsumi K, Suzuki T (2022) Multi-omics analysis of right ventricles in rat models of pulmonary arterial hypertension: consideration of mitochondrial biogenesis by chrysin. Int J Mol Med. https://doi.org/10.3892/ijmm.2022.5124

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lau CH, Chan CM, Chan YW, Lau KM, Lau TW, Lam FC, Law WT, Che CT, Leung PC, Fung KP, Ho YY, Lau CBS (2007) Pharmacological investigations of the anti-diabetic effect of cortex moutan and its active component paeonol. Phytomedicine 14:778–784. https://doi.org/10.1016/j.phymed.2007.01.007

    Article  CAS  PubMed  Google Scholar 

  50. Wang D, Du Y, Xu H, Pan H, Wang R (2019) Paeonol protects mitochondrial injury and prevents pulmonary vascular remodeling in hypoxia. Respir Physiol Neurobiol. https://doi.org/10.1016/j.resp.2019.103252

    Article  PubMed  PubMed Central  Google Scholar 

  51. Legchenko E, Chouvarine P, Borchert P, Fernandez-Gonzalez A, Snay E, Meier M, Maegel L, Mitsialis SA, Rog-Zielinska EA, Kourembanas S, Jonigk D, Hansmann G (2018) PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aao0303

    Article  PubMed  Google Scholar 

  52. Zhang B, Niu W, Xu D, Li Y, Liu M, Wang Y, Luo Y, Zhao P, Liu Y, Dong M, Sun R, Dong H, Li Z (2014) Oxymatrine prevents hypoxia- and monocrotaline-induced pulmonary hypertension in rats. Free Radic Biol Med 69:198–207. https://doi.org/10.1016/j.freeradbiomed.2014.01.013

    Article  CAS  PubMed  Google Scholar 

  53. Shafiq M, Lone ZR, Bharati P, Mahapatra S, Rai P, Khandelwal N, Gaikwad AN, Jagavelu K, Hanif K (2022) Pyrroloquinoline quinone (PQQ) improves pulmonary hypertension by regulating mitochondrial and metabolic functions. Pulm Pharmacol Ther 76:102156. https://doi.org/10.1016/j.pupt.2022.102156

    Article  CAS  PubMed  Google Scholar 

  54. Culley MK, Chan SY (2018) Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains. J Clin Invest 128:3704–3715. https://doi.org/10.1172/jci120847

    Article  PubMed  PubMed Central  Google Scholar 

  55. Ashrafi G, Schwarz TL (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 20:31–42. https://doi.org/10.1038/cdd.2012.81

    Article  CAS  PubMed  Google Scholar 

  56. Chen G, Kroemer G, Kepp O (2020) Mitophagy: an emerging role in aging and age-associated diseases. Front Cell Dev Biol 8:200. https://doi.org/10.3389/fcell.2020.00200

    Article  PubMed  PubMed Central  Google Scholar 

  57. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, LaVoie MJ, Schwarz TL (2011) PINK1 and Parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147:893–906. https://doi.org/10.1016/j.cell.2011.10.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Salazar C, Ruiz-Hincapie P, Ruiz LM (2018) The interplay among PINK1/PARKIN/Dj-1 network during mitochondrial quality control in cancer biology: protein interaction analysis. Cells. https://doi.org/10.3390/cells7100154

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kim Y, Park J, Kim S, Song S, Kwon SK, Lee SH, Kitada T, Kim JM, Chung J (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377:975–980. https://doi.org/10.1016/j.bbrc.2008.10.104

    Article  CAS  PubMed  Google Scholar 

  60. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Øvervatn A, Bjørkøy G, Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282:24131–24145. https://doi.org/10.1074/jbc.M702824200

    Article  CAS  PubMed  Google Scholar 

  61. Van Humbeeck C, Cornelissen T, Hofkens H, Mandemakers W, Gevaert K, De Strooper B, Vandenberghe W (2011) Parkin interacts with Ambra1 to induce mitophagy. J Neurosci 31:10249–10261. https://doi.org/10.1523/jneurosci.1917-11.2011

    Article  PubMed  PubMed Central  Google Scholar 

  62. Aggarwal S, Mannam P, Zhang J (2016) Differential regulation of autophagy and mitophagy in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol 311:L433–L452. https://doi.org/10.1152/ajplung.00128.2016

    Article  PubMed  PubMed Central  Google Scholar 

  63. Linqing L, Yuhan Q, Erfei L, Yong Q, Dong W, Chengchun T, Gaoliang Y, Bo L (2021) Hypoxia-induced PINK1/Parkin-mediated mitophagy promotes pulmonary vascular remodeling. Biochem Biophys Res Commun 534:568–575. https://doi.org/10.1016/j.bbrc.2020.11.040

    Article  CAS  PubMed  Google Scholar 

  64. Saraji A, Sydykov A, Schäfer K, Garcia-Castro CF, Henneke I, Alebrahimdehkordi N, Kosanovic D, Hadzic S, Guenther A, Hecker M, Ghofrani HA, Seeger W, Schermuly RT, Weissmann N, Sommer N, Pak O (2021) PINK1-mediated mitophagy contributes to pulmonary vascular remodeling in pulmonary hypertension. Am J Respir Cell Mol Biol 65:226–228. https://doi.org/10.1165/rcmb.2021-0082LE

    Article  CAS  PubMed  Google Scholar 

  65. Dasgupta A, Chen KH, Lima PDA, Mewburn J, Wu D, Al-Qazazi R, Jones O, Tian L, Potus F, Bonnet S, Archer SL (2021) PINK1-induced phosphorylation of mitofusin 2 at serine 442 causes its proteasomal degradation and promotes cell proliferation in lung cancer and pulmonary arterial hypertension. Faseb J 35:e21771. https://doi.org/10.1096/fj.202100361R

    Article  CAS  PubMed  Google Scholar 

  66. Rehman R, Vellarikkal SK, Dieffenbach PB, Lam HC, Filippakis C, Fredenburgh LE (2021) Impaired mitophagy and reduced parkin expression in human pulmonary arterial smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH). Circulation. https://doi.org/10.1161/circ.144.suppl_1.14210

    Article  PubMed  Google Scholar 

  67. Fang X, Xie M, Liu X, He Y (2022) REDD1 gene knockout alleviates vascular smooth muscle cell remodeling in pulmonary hypertension. Am J Transl Res 14:1578–1591

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrychowski MP, Sviderskiy VO, Olszewski JL, Koerber JT, Xie T, Beausoleil SA, Wells JA, Gygi SP, Schulman BA, Harper JW (2014) Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell 56:360–375. https://doi.org/10.1016/j.molcel.2014.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW (2013) Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496:372–376. https://doi.org/10.1038/nature12043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dorn GW 2nd, Kitsis RN (2015) The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circ Res 116:167–182. https://doi.org/10.1161/circresaha.116.303554

    Article  CAS  PubMed  Google Scholar 

  71. Wei Y, Chiang WC, Sumpter R Jr, Mishra P, Levine B (2017) Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 168:224-238.e10. https://doi.org/10.1016/j.cell.2016.11.042

    Article  CAS  PubMed  Google Scholar 

  72. Puri R, Cheng XT, Lin MY, Huang N, Sheng ZH (2019) Mul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts. Nat Commun 10:3645. https://doi.org/10.1038/s41467-019-11636-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li S, Zhou Y, Gu X, Zhang X, Jia Z (2021) NLRX1/FUNDC1/NIPSNAP1-2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury. Cell Prolif 54:e12986. https://doi.org/10.1111/cpr.12986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yoo SM, Yamashita SI, Kim H, Na D, Lee H, Kim SJ, Cho DH, Kanki T, Jung YK (2020) FKBP8 LIRL-dependent mitochondrial fragmentation facilitates mitophagy under stress conditions. Faseb j 34:2944–2957. https://doi.org/10.1096/fj.201901735R

    Article  CAS  PubMed  Google Scholar 

  75. Chinnadurai G, Vijayalingam S, Gibson SB (2008) BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. Oncogene 27(Suppl 1):S114–S127. https://doi.org/10.1038/onc.2009.49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, Mazure NM (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29:2570–2581. https://doi.org/10.1128/mcb.00166-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhu Y, Massen S, Terenzio M, Lang V, Chen-Lindner S, Eils R, Novak I, Dikic I, Hamacher-Brady A, Brady NR (2013) Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. J Biol Chem 288:1099–1113. https://doi.org/10.1074/jbc.M112.399345

    Article  CAS  PubMed  Google Scholar 

  78. Deng Y, Wu W, Guo S, Chen Y, Liu C, Gao X, Wei B (2017) Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension. Respir Res 18:53. https://doi.org/10.1186/s12931-017-0536-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL (2001) HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61:6669–6673

    CAS  PubMed  Google Scholar 

  80. Yuan Y, Zheng Y, Zhang X, Chen Y, Wu X, Wu J, Shen Z, Jiang L, Wang L, Yang W, Luo J, Qin Z, Hu W, Chen Z (2017) BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2. Autophagy 13:1754–1766. https://doi.org/10.1080/15548627.2017.1357792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G (2015) The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet 24:2528–2538. https://doi.org/10.1093/hmg/ddv017

    Article  CAS  PubMed  Google Scholar 

  82. Ning H, Deng J, Chen F, Liu Y, Kong D, Shan L, Zhang Z, Hu T (2020) β-arrestin1 inhibits hypoxic injury-induced autophagy in human pulmonary artery endothelial cells via the Akt/mTOR signaling pathway. Int J Biochem Cell Biol 125:105791. https://doi.org/10.1016/j.biocel.2020.105791

    Article  CAS  PubMed  Google Scholar 

  83. Chen G, Han Z, Feng D, Chen Y, Chen L, Wu H, Huang L, Zhou C, Cai X, Fu C, Duan L, Wang X, Liu L, Liu X, Shen Y, Zhu Y, Chen Q (2014) A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell 54:362–377. https://doi.org/10.1016/j.molcel.2014.02.034

    Article  CAS  PubMed  Google Scholar 

  84. Liu R, Xu C, Zhang W, Cao Y, Ye J, Li B, Jia S, Weng L, Liu Y, Liu L, Zheng M (2022) FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia. Cell Death Dis 13:634. https://doi.org/10.1038/s41419-022-05091-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Pak O, Sommer N, Hoeres T, Bakr A, Waisbrod S, Sydykov A, Haag D, Esfandiary A, Kojonazarov B, Veit F, Fuchs B, Weisel FC, Hecker M, Schermuly RT, Grimminger F, Ghofrani HA, Seeger W, Weissmann N (2013) Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model. Am J Respir Cell Mol Biol 49:358–367. https://doi.org/10.1165/rcmb.2012-0361OC

    Article  CAS  PubMed  Google Scholar 

  86. Dromparis P, Paulin R, Sutendra G, Qi AC, Bonnet S, Michelakis ED (2013) Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. Circ Res 113:126–136. https://doi.org/10.1161/circresaha.112.300699

    Article  CAS  PubMed  Google Scholar 

  87. Haslip M, Dostanic I, Huang Y, Zhang Y, Russell KS, Jurczak MJ, Mannam P, Giordano F, Erzurum SC, Lee PJ (2015) Endothelial uncoupling protein 2 regulates mitophagy and pulmonary hypertension during intermittent hypoxia. Arterioscler Thromb Vasc Biol 35:1166–1178. https://doi.org/10.1161/atvbaha.114.304865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li T, Li K, Zhang S, Wang Y, Xu Y, Cronin SJF, Sun Y, Zhang Y, Xie C, Rodriguez J, Zhou K, Hagberg H, Mallard C, Wang X, Penninger JM, Kroemer G, Blomgren K, Zhu C (2020) Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice. Cell Death Dis. https://doi.org/10.1038/s41419-020-2280-z

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ma C, Wang X, He S, Zhang L, Bai J, Qu L, Qi J, Zheng X, Zhu X, Mei J, Guan X, Yuan H, Zhu D (2022) Ubiquitinated AIF is a major mediator of hypoxia-induced mitochondrial dysfunction and pulmonary artery smooth muscle cell proliferation. Cell Biosci. https://doi.org/10.1186/s13578-022-00744-3

    Article  PubMed  PubMed Central  Google Scholar 

  90. Choi CY, Vo MT, Nicholas J, Choi YB (2022) Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis. Cell Death Differ 29:451–464. https://doi.org/10.1038/s41418-021-00868-y

    Article  CAS  PubMed  Google Scholar 

  91. Panepinto JC, Misener AL, Oliver BG, Hu G, Park YD, Shin S, White TC, Williamson PR (2010) Overexpression of TUF1 restores respiratory growth and fluconazole sensitivity to a cryptococcus neoformans vad1Delta mutant. Microbiology (Reading) 156:2558–2565. https://doi.org/10.1099/mic.0.035923-0

    Article  CAS  PubMed  Google Scholar 

  92. Wei R, Lv X, Fang C, Liu C, Ma Z, Liu K (2022) Silencing TUFM inhibits development of monocrotaline-induced pulmonary hypertension by regulating mitochondrial autophagy via AMPK/mTOR signal pathway. Oxid Med Cell Longev 2022:4931611. https://doi.org/10.1155/2022/4931611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang M, Luo P, Shi W, Guo J, Huo S, Yan D, Peng L, Zhang C, Lv J, Lin L, Li S (2021) S-nitroso-L-cysteine ameliorated pulmonary hypertension in the MCT-induced rats through anti-ROS and anti-inflammatory pathways. Oxid Med Cell Longev 2021:6621232. https://doi.org/10.1155/2021/6621232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lu Y, Wu J, Sun Y, Xin L, Jiang Z, Lin H, Zhao M, Cui X (2020) Qiliqiangxin prevents right ventricular remodeling by inhibiting apoptosis and improving metabolism reprogramming with pulmonary arterial hypertension. Am J Transl Res 12:5655–5669

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Dasgupta A, Wu D, Tian L, Xiong PY, Dunham-Snary KJ, Chen KH, Alizadeh E, Motamed M, Potus F, Hindmarch CCT, Archer SL (2020) Mitochondria in the pulmonary vasculature in health and disease: oxygen-sensing, metabolism, and dynamics. Compr Physiol 10:713–765. https://doi.org/10.1002/cphy.c190027

    Article  PubMed  Google Scholar 

  96. Lou G, Palikaras K, Lautrup S, Scheibye-Knudsen M, Tavernarakis N, Fang EF (2020) Mitophagy and neuroprotection. Trends Mol Med 26:8–20. https://doi.org/10.1016/j.molmed.2019.07.002

    Article  CAS  PubMed  Google Scholar 

  97. Tilokani L, Nagashima S, Paupe V, Prudent J (2018) Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem 62:341–360. https://doi.org/10.1042/ebc20170104

    Article  PubMed  PubMed Central  Google Scholar 

  98. Santos EW, Khatoon S, Di Mise A, Zheng YM, Wang YX (2023) Mitochondrial dynamics in pulmonary hypertension. Biomedicines. https://doi.org/10.3390/biomedicines12010053

    Article  PubMed  PubMed Central  Google Scholar 

  99. Korobova F, Ramabhadran V, Higgs HN (2013) An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science 339:464–467. https://doi.org/10.1126/science.1228360

    Article  CAS  PubMed  Google Scholar 

  100. Manor U, Bartholomew S, Golani G, Christenson E, Kozlov M, Higgs H, Spudich J, Lippincott-Schwartz J (2015) A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division. Elife. https://doi.org/10.7554/eLife.08828

    Article  PubMed  PubMed Central  Google Scholar 

  101. Korobova F, Gauvin TJ, Higgs HN (2014) A role for myosin II in mammalian mitochondrial fission. Curr Biol 24:409–414. https://doi.org/10.1016/j.cub.2013.12.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Li S, Xu S, Roelofs BA, Boyman L, Lederer WJ, Sesaki H, Karbowski M (2015) Transient assembly of F-actin on the outer mitochondrial membrane contributes to mitochondrial fission. J Cell Biol 208:109–123. https://doi.org/10.1083/jcb.201404050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Fonseca TB, Sánchez-Guerrero Á, Milosevic I, Raimundo N (2019) Mitochondrial fission requires DRP1 but not dynamins. Nature 570:E34-e42. https://doi.org/10.1038/s41586-019-1296-y

    Article  CAS  PubMed  Google Scholar 

  104. Scarpelli PH, Tessarin-Almeida G, Viçoso KL, Lima WR, Borges-Pereira L, Meissner KA, Wrenger C, Raffaello A, Rizzuto R, Pozzan T, Garcia CRS (2019) Melatonin activates FIS1, DYN1, and DYN2 Plasmodium falciparum related-genes for mitochondria fission: mitoemerald-GFP as a tool to visualize mitochondria structure. J Pineal Res 66:e12484. https://doi.org/10.1111/jpi.12484

    Article  CAS  PubMed  Google Scholar 

  105. Panchal K, Tiwari AK (2019) Mitochondrial dynamics, a key executioner in neurodegenerative diseases. Mitochondrion 47:151–173. https://doi.org/10.1016/j.mito.2018.11.002

    Article  CAS  PubMed  Google Scholar 

  106. Shen Q, Yamano K, Head BP, Kawajiri S, Cheung JT, Wang C, Cho JH, Hattori N, Youle RJ, van der Bliek AM (2014) Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Mol Biol Cell 25:145–159. https://doi.org/10.1091/mbc.E13-09-0525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Losón OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667. https://doi.org/10.1091/mbc.E12-10-0721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Marsboom G, Toth PT, Ryan JJ, Hong Z, Wu X, Fang YH, Thenappan T, Piao L, Zhang HJ, Pogoriler J, Chen Y, Morrow E, Weir EK, Rehman J, Archer SL (2012) Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res 110:1484–1497. https://doi.org/10.1161/circresaha.111.263848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Dai Y, Yu B, Ai D, Yuan L, Wang X, Huo R, Fu X, Chen S, Chen C (2020) Mitochondrial fission-mediated lung development in newborn rats with hyperoxia-induced bronchopulmonary dysplasia with pulmonary hypertension. Front Pediatr 8:619853. https://doi.org/10.3389/fped.2020.619853

    Article  PubMed  Google Scholar 

  110. Wang F, Zhen Y, Si C, Wang C, Pan L, Chen Y, Liu X, Kong J, Nie Q, Sun M, Han Y, Ye Z, Liu P, Wen J (2022) WNT5B promotes vascular smooth muscle cell dedifferentiation via mitochondrial dynamics regulation in chronic thromboembolic pulmonary hypertension. J Cell Physiol 237:789–803. https://doi.org/10.1002/jcp.30543

    Article  CAS  PubMed  Google Scholar 

  111. Feng W, Wang J, Yan X, Zhang Q, Chai L, Wang Q, Shi W, Chen Y, Liu J, Qu Z, Li S, Xie X, Li M (2021) ERK/Drp1-dependent mitochondrial fission contributes to HMGB1-induced autophagy in pulmonary arterial hypertension. Cell Prolif 54:e13048. https://doi.org/10.1111/cpr.13048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sharp WW, Fang YH, Han M, Zhang HJ, Hong Z, Banathy A, Morrow E, Ryan JJ, Archer SL (2014) Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. Faseb J 28:316–326. https://doi.org/10.1096/fj.12-226225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Trindade F, Vitorino R, Leite-Moreira A, Falcão-Pires I (2019) Pericardial fluid: an underrated molecular library of heart conditions and a potential vehicle for cardiac therapy. Basic Res Cardiol 114:10. https://doi.org/10.1007/s00395-019-0716-3

    Article  PubMed  Google Scholar 

  114. Galvan DL, Long J, Green N, Chang BH, Lin JS, Schumacker P, Truong LD, Overbeek P, Danesh FR (2019) Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic mice. J Clin Investig 129:2807–2823. https://doi.org/10.1172/jci127277

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wells RC, Picton LK, Williams SCP, Tan FJ, Hill RB (2007) Direct binding of the dynamin-like GTPase, Dnm1, to mitochondrial dynamics protein Fis1 is negatively regulated by the Fis1 N-terminal arm. J Biol Chem 282:33769–33775. https://doi.org/10.1074/jbc.M700807200

    Article  CAS  PubMed  Google Scholar 

  116. Tian L, Potus F, Wu D, Dasgupta A, Chen KH, Mewburn J, Lima P, Archer SL (2018) Increased Drp1-mediated mitochondrial fission promotes proliferation and collagen production by right ventricular fibroblasts in experimental pulmonary arterial hypertension. Front Physiol 9:828. https://doi.org/10.3389/fphys.2018.00828

    Article  PubMed  PubMed Central  Google Scholar 

  117. Tian L, Neuber-Hess M, Mewburn J, Dasgupta A, Dunham-Snary K, Wu D, Chen KH, Hong Z, Sharp WW, Kutty S, Archer SL (2017) Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension. J Mol Med (Berl) 95:381–393. https://doi.org/10.1007/s00109-017-1522-8

    Article  CAS  PubMed  Google Scholar 

  118. Zhou H, Wang J, Zhu P, Zhu H, Toan S, Hu S, Ren J, Chen Y (2018) NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res Cardiol 113:23. https://doi.org/10.1007/s00395-018-0682-1

    Article  CAS  PubMed  Google Scholar 

  119. Loson OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667. https://doi.org/10.1091/mbc.E12-10-0721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhang Z, Liu L, Wu S, Xing D (2016) Drp1, Mff, Fis1, and MiD51 are coordinated to mediate mitochondrial fission during UV irradiation-induced apoptosis. Faseb j 30:466–476. https://doi.org/10.1096/fj.15-274258

    Article  CAS  PubMed  Google Scholar 

  121. Xiong PY, Tian L, Dunham-Snary KJ, Chen KH, Mewburn JD, Neuber-Hess M, Martin A, Dasgupta A, Potus F, Archer SL (2018) Biventricular increases in mitochondrial fission mediator (MiD51) and proglycolytic pyruvate kinase (PKM2) isoform in experimental group 2 pulmonary hypertension-novel mitochondrial abnormalities. Front Cardiovasc Med 5:195. https://doi.org/10.3389/fcvm.2018.00195

    Article  CAS  PubMed  Google Scholar 

  122. Zhang L, Ma C, Zhang C, Ma M, Zhang F, Zhang L, Chen Y, Cao F, Li S, Zhu D (2016) Reactive oxygen species effect PASMCs apoptosis via regulation of dynamin-related protein 1 in hypoxic pulmonary hypertension. Histochem Cell Biol 146:71–84. https://doi.org/10.1007/s00418-016-1424-9

    Article  CAS  PubMed  Google Scholar 

  123. Parra V, Bravo-Sagua R, Norambuena-Soto I, Hernández-Fuentes CP, Gómez-Contreras AG, Verdejo HE, Mellado R, Chiong M, Lavandero S, Castro PF (2017) Inhibition of mitochondrial fission prevents hypoxia-induced metabolic shift and cellular proliferation of pulmonary arterial smooth muscle cells. Biochim Biophys Acta Mol Basis Dis 1863:2891–2903. https://doi.org/10.1016/j.bbadis.2017.07.018

    Article  CAS  PubMed  Google Scholar 

  124. Shen T, Wang N, Yu X, Shi J, Li Q, Zhang C, Fu L, Wang S, Xing Y, Zheng X, Yu L, Zhu D (2015) The critical role of dynamin-related protein 1 in hypoxia-induced pulmonary vascular angiogenesis. J Cell Biochem 116:1993–2007. https://doi.org/10.1002/jcb.25154

    Article  CAS  PubMed  Google Scholar 

  125. Hong Z, Chen KH, DasGupta A, Potus F, Dunham-Snary K, Bonnet S, Tian L, Fu J, Breuils-Bonnet S, Provencher S, Wu D, Mewburn J, Ormiston ML, Archer SL (2017) MicroRNA-138 and microRNA-25 down-regulate mitochondrial calcium uniporter, causing the pulmonary arterial hypertension cancer phenotype. Am J Respir Crit Care Med 195:515–529. https://doi.org/10.1164/rccm.201604-0814OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Chen KH, Dasgupta A, Lin J, Potus F, Bonnet S, Iremonger J, Fu J, Mewburn J, Wu D, Dunham-Snary K, Theilmann AL, Jing ZC, Hindmarch C, Ormiston ML, Lawrie A, Archer SL (2018) Epigenetic dysregulation of the dynamin-related protein 1 binding partners MiD49 and MiD51 increases mitotic mitochondrial fission and promotes pulmonary arterial hypertension: mechanistic and therapeutic implications. Circulation 138:287–304. https://doi.org/10.1161/circulationaha.117.031258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Huang CX, Jiang ZX, Du DY, Zhang ZM, Liu Y, Li YT (2022) The MFF-SIRT1/3 axis, regulated by miR-340-5p, restores mitochondrial homeostasis of hypoxia-induced pulmonary artery smooth muscle cells. Lab Invest 102:515–523. https://doi.org/10.1038/s41374-022-00730-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ayala A, Muñoz MF, Argüelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014:360438. https://doi.org/10.1155/2014/360438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhao Y, Wang B, Zhang J, He D, Zhang Q, Pan C, Yuan Q, Shi Y, Tang H, Xu F, Wei S, Chen Y (2019) ALDH2 (aldehyde dehydrogenase 2) protects against hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol 39:2303–2319. https://doi.org/10.1161/atvbaha.119.312946

    Article  CAS  PubMed  Google Scholar 

  130. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ (2002) Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 165:800–804. https://doi.org/10.1164/ajrccm.165.6.2106079

    Article  PubMed  Google Scholar 

  131. Waxman A, Restrepo-Jaramillo R, Thenappan T, Ravichandran A, Engel P, Bajwa A, Allen R, Feldman J, Argula R, Smith P, Rollins K, Deng C, Peterson L, Bell H, Tapson V, Nathan SD (2021) Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med 384:325–334. https://doi.org/10.1056/NEJMoa2008470

    Article  CAS  PubMed  Google Scholar 

  132. Abu-Hanna J, Taanman JW, Abraham D, Clapp L (2018) Impact of treprostinil on dynamin-related protein 1 (DRP1) and mitochondrial fragmentation in pulmonary arterial hypertension (PAH). Eur Respir J. https://doi.org/10.1183/13993003.congress-2018.PA3059

    Article  Google Scholar 

  133. Goldenberg NM, Hu Y, Hu X, Volchuk A, Zhao YD, Kucherenko MM, Knosalla C, de Perrot M, Tracey KJ, Al-Abed Y, Steinberg BE, Kuebler WM (2019) Therapeutic targeting of high-mobility group box-1 in pulmonary arterial hypertension. Am J Respir Crit Care Med 199:1566–1569. https://doi.org/10.1164/rccm.201808-1597LE

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wu YC, Wang WT, Lee SS, Kuo YR, Wang YC, Yen SJ, Lee MY, Yeh JL (2019) Glucagon-like peptide-1 receptor agonist attenuates autophagy to ameliorate pulmonary arterial hypertension through Drp1/NOX- and Atg-5/Atg-7/beclin-1/LC3β pathways. Int J Mol Sci. https://doi.org/10.3390/ijms20143435

    Article  PubMed  PubMed Central  Google Scholar 

  135. Zhuan B, Wang X, Wang MD, Li ZC, Yuan Q, Xie J, Yang Z (2020) Hypoxia induces pulmonary artery smooth muscle dysfunction through mitochondrial fragmentation-mediated endoplasmic reticulum stress. Aging (Albany NY) 12:23684–23697. https://doi.org/10.18632/aging.103892

    Article  PubMed  Google Scholar 

  136. Chakrabarti R, Higgs HN (2021) Revolutionary view of two ways to split a mitochondrion. Nature 593:346–347. https://doi.org/10.1038/d41586-021-01173-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR, Nunnari J (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14:193–204. https://doi.org/10.1016/j.devcel.2007.11.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Rojo M, Legros F, Chateau D, Lombès A (2002) Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci 115:1663–1674. https://doi.org/10.1242/jcs.115.8.1663

    Article  CAS  PubMed  Google Scholar 

  139. Gao S, Hu J (2021) Mitochondrial fusion: the machineries in and out. Trends Cell Biol 31:62–74. https://doi.org/10.1016/j.tcb.2020.09.008

    Article  CAS  PubMed  Google Scholar 

  140. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26:211–215. https://doi.org/10.1038/79944

    Article  CAS  PubMed  Google Scholar 

  141. Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, Astarie-Dequeker C, Lasquellec L, Arnaud B, Ducommun B, Kaplan J, Hamel CP (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26:207–210. https://doi.org/10.1038/79936

    Article  CAS  PubMed  Google Scholar 

  142. Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Arnauné-Pelloquin L, Davezac N, Mils V, Miquel MC, Rojo M, Belenguer P (2016) Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis 90:3–19. https://doi.org/10.1016/j.nbd.2015.10.011

    Article  CAS  PubMed  Google Scholar 

  143. Silva Ramos E, Motori E, Brüser C, Kühl I, Yeroslaviz A, Ruzzenente B, Kauppila JHK, Busch JD, Hultenby K, Habermann BH, Jakobs S, Larsson NG, Mourier A (2019) Mitochondrial fusion is required for regulation of mitochondrial DNA replication. PLoS Genet 15:e1008085. https://doi.org/10.1371/journal.pgen.1008085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chi AY, Waypa GB, Mungai PT, Schumacker PT (2010) Prolonged hypoxia increases ROS signaling and RhoA activation in pulmonary artery smooth muscle and endothelial cells. Antioxid Redox Signal 12:603–610. https://doi.org/10.1089/ars.2009.2861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Marshall JD, Bazan I, Zhang Y, Fares WH, Lee PJ (2018) Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both. Am J Physiol Lung Cell Mol Physiol 314:L782-l796. https://doi.org/10.1152/ajplung.00331.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Fang X, Chen X, Zhong G, Chen Q, Hu C (2016) Mitofusin 2 downregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PI3K/Akt and mitochondrial apoptosis pathways. J Cardiovasc Pharmacol 67:164–174. https://doi.org/10.1097/fjc.0000000000000333

    Article  CAS  PubMed  Google Scholar 

  147. Chen IC, Liu YC, Wu YH, Lo SH, Wang SC, Li CY, Dai ZK, Hsu JH, Yeh CY, Tseng YH (2022) Proteasome inhibitors decrease the viability of pulmonary arterial smooth muscle cells by restoring mitofusin-2 expression under hypoxic conditions. Biomedicines. https://doi.org/10.3390/biomedicines10040873

    Article  PubMed  PubMed Central  Google Scholar 

  148. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610. https://doi.org/10.1038/nature07534

    Article  CAS  PubMed  Google Scholar 

  149. Sheng R, Gu ZL, Xie ML, Zhou WX, Guo CY (2010) Epigallocatechin gallate protects H9c2 cardiomyoblasts against hydrogen dioxides- induced apoptosis and telomere attrition. Eur J Pharmacol 641:199–206. https://doi.org/10.1016/j.ejphar.2010.05.054

    Article  CAS  PubMed  Google Scholar 

  150. Riegsecker S, Wiczynski D, Kaplan MJ, Ahmed S (2013) Potential benefits of green tea polyphenol EGCG in the prevention and treatment of vascular inflammation in rheumatoid arthritis. Life Sci 93:307–312. https://doi.org/10.1016/j.lfs.2013.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Legeay S, Rodier M, Fillon L, Faure S, Clere N (2015) Epigallocatechin gallate: a review of its beneficial properties to prevent metabolic syndrome. Nutrients 7:5443–5468. https://doi.org/10.3390/nu7075230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zhu TT, Zhang WF, Luo P, He F, Ge XY, Zhang Z, Hu CP (2017) Epigallocatechin-3-gallate ameliorates hypoxia-induced pulmonary vascular remodeling by promoting mitofusin-2-mediated mitochondrial fusion. Eur J Pharmacol 809:42–51. https://doi.org/10.1016/j.ejphar.2017.05.003

    Article  CAS  PubMed  Google Scholar 

  153. Zhang W, Shu C, Li Q, Li M, Li X (2015) Adiponectin affects vascular smooth muscle cell proliferation and apoptosis through modulation of the mitofusin-2-mediated Ras-Raf-Erk1/2 signaling pathway. Mol Med Rep 12:4703–4707. https://doi.org/10.3892/mmr.2015.3899

    Article  CAS  PubMed  Google Scholar 

  154. Kowaltowski AJ, Menezes-Filho SL, Assali EA, Gonçalves IG, Cabral-Costa JV, Abreu P, Miller N, Nolasco P, Laurindo FRM, Bruni-Cardoso A, Shirihai OS (2019) Mitochondrial morphology regulates organellar Ca(2+) uptake and changes cellular Ca(2+) homeostasis. Faseb j 33:13176–13188. https://doi.org/10.1096/fj.201901136R

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Robert P, Nguyen PMC, Richard A, Grenier C, Chevrollier A, Munier M, Grimaud L, Proux C, Champin T, Lelièvre E, Sarzi E, Vessières E, Henni S, Prunier D, Reynier P, Lenaers G, Fassot C, Henrion D, Loufrani L (2021) Protective role of the mitochondrial fusion protein OPA1 in hypertension. Faseb j 35:e21678. https://doi.org/10.1096/fj.202000238RRR

    Article  CAS  PubMed  Google Scholar 

  156. Lu Z, Li S, Zhao S, Fa X (2016) Upregulated miR-17 regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation and apoptosis by targeting mitofusin 2. Med Sci Monit 22:3301–3308. https://doi.org/10.12659/msm.900487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Zhang D, Ma C, Li S, Ran Y, Chen J, Lu P, Shi S, Zhu D (2012) Effect of Mitofusin 2 on smooth muscle cells proliferation in hypoxic pulmonary hypertension. Microvasc Res 84:286–296. https://doi.org/10.1016/j.mvr.2012.06.010

    Article  CAS  PubMed  Google Scholar 

  158. Ma C, Zhang C, Ma M, Zhang L, Zhang L, Zhang F, Chen Y, Cao F, Li M, Wang G, Shen T, Yao H, Liu Y, Pan Z, Song S, Zhu D (2017) MiR-125a regulates mitochondrial homeostasis through targeting mitofusin 1 to control hypoxic pulmonary vascular remodeling. J Mol Med (Berl) 95:977–993. https://doi.org/10.1007/s00109-017-1541-5

    Article  CAS  PubMed  Google Scholar 

  159. Zhou G, Chen T, Raj JU (2015) MicroRNAs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 52:139–151. https://doi.org/10.1165/rcmb.2014-0166TR

    Article  PubMed  PubMed Central  Google Scholar 

  160. Huang S, Chen Z, Wu W, Wang M, Wang R, Cui J, Li W, Wang S (2018) MicroRNA-31 promotes arterial smooth muscle cell proliferation and migration by targeting mitofusin-2 in arteriosclerosis obliterans of the lower extremitie. Exp Ther Med 15:633–640. https://doi.org/10.3892/etm.2017.5453

    Article  CAS  PubMed  Google Scholar 

  161. Joshi SR, Dhagia V, Gairhe S, Edwards JG, McMurtry IF, Gupte SA (2016) MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 311:H689–H698. https://doi.org/10.1152/ajpheart.00264.2016

    Article  PubMed  PubMed Central  Google Scholar 

  162. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465. https://doi.org/10.1038/290457a0

    Article  CAS  PubMed  Google Scholar 

  163. Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N (2009) Importing mitochondrial proteins: machineries and mechanisms. Cell 138:628–644. https://doi.org/10.1016/j.cell.2009.08.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Yoneda T, Benedetti C, Urano F, Clark SG, Harding HP, Ron D (2004) Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J Cell Sci 117:4055–4066. https://doi.org/10.1242/jcs.01275

    Article  CAS  PubMed  Google Scholar 

  165. Curtis JM, Hahn WS, Stone MD, Inda JJ, Droullard DJ, Kuzmicic JP, Donoghue MA, Long EK, Armien AG, Lavandero S, Arriaga E, Griffin TJ, Bernlohr DA (2012) Protein carbonylation and adipocyte mitochondrial function. J Biol Chem 287:32967–32980. https://doi.org/10.1074/jbc.M112.400663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Koyama M, Furuhashi M, Ishimura S, Mita T, Fuseya T, Okazaki Y, Yoshida H, Tsuchihashi K, Miura T (2014) Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 306:H1314–H1323. https://doi.org/10.1152/ajpheart.00869.2013

    Article  CAS  PubMed  Google Scholar 

  167. Hu L, Zhao R, Liu Q, Li Q (2020) New insights into heat shock protein 90 in the pathogenesis of pulmonary arterial hypertension. Front Physiol 11:1081. https://doi.org/10.3389/fphys.2020.01081

    Article  PubMed  PubMed Central  Google Scholar 

  168. Wang GK, Li SH, Zhao ZM, Liu SX, Zhang GX, Yang F, Wang Y, Wu F, Zhao XX, Xu ZY (2016) Inhibition of heat shock protein 90 improves pulmonary arteriole remodeling in pulmonary arterial hypertension. Oncotarget 7:54263–54273. https://doi.org/10.18632/oncotarget.10855

    Article  PubMed  PubMed Central  Google Scholar 

  169. Boucherat O, Peterlini T, Bourgeois A, Nadeau V, Breuils-Bonnet S, Boilet-Molez S, Potus F, Meloche J, Chabot S, Lambert C, Tremblay E, Chae YC, Altieri DC, Sutendra G, Michelakis ED, Paulin R, Provencher S, Bonnet S (2018) Mitochondrial HSP90 accumulation promotes vascular remodeling in pulmonary arterial hypertension. Am J Respir Crit Care Med 198:90–103. https://doi.org/10.1164/rccm.201708-1751OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337:587–590. https://doi.org/10.1126/science.1223560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Melber A, Haynes CM (2018) UPR(mt) regulation and output: a stress response mediated by mitochondrial-nuclear communication. Cell Res 28:281–295. https://doi.org/10.1038/cr.2018.16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Martin J, Mahlke K, Pfanner N (1991) Role of an energized inner membrane in mitochondrial protein import. Delta psi drives the movement of presequences. J Biol Chem 266:18051–18057

    Article  CAS  PubMed  Google Scholar 

  173. Rolland SG, Schneid S, Schwarz M, Rackles E, Fischer C, Haeussler S, Regmi SG, Yeroslaviz A, Habermann B, Mokranjac D, Lambie E, Conradt B (2019) Compromised mitochondrial protein import acts as a signal for UPR(mt). Cell Rep 28:1659-1669e5. https://doi.org/10.1016/j.celrep.2019.07.049

    Article  CAS  PubMed  Google Scholar 

  174. Yeager ME, Reddy MB, Nguyen CM, Colvin KL, Ivy DD, Stenmark KR (2012) Activation of the unfolded protein response is associated with pulmonary hypertension. Pulm Circ 2:229–240. https://doi.org/10.4103/2045-8932.97613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Scull CM, Tabas I (2011) Mechanisms of ER stress-induced apoptosis in atherosclerosis. Arterioscler Thromb Vasc Biol 31:2792–2797. https://doi.org/10.1161/atvbaha.111.224881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Fiorese CJ, Schulz AM, Lin YF, Rosin N, Pellegrino MW, Haynes CM (2016) The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr Biol 26:2037–2043. https://doi.org/10.1016/j.cub.2016.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Michel S, Canonne M, Arnould T, Renard P (2015) Inhibition of mitochondrial genome expression triggers the activation of CHOP-10 by a cell signaling dependent on the integrated stress response but not the mitochondrial unfolded protein response. Mitochondrion 21:58–68. https://doi.org/10.1016/j.mito.2015.01.005

    Article  CAS  PubMed  Google Scholar 

  178. Pathak VK, Schindler D, Hershey JW (1988) Generation of a mutant form of protein synthesis initiation factor eIF-2 lacking the site of phosphorylation by eIF-2 kinases. Mol Cell Biol 8:993–995. https://doi.org/10.1128/mcb.8.2.993-995.1988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Wang JL, Liu H, Jing ZC, Zhao F, Zhou R (2022) 18β-Glycyrrhetinic acid ameliorates endoplasmic reticulum stress-induced inflammation in pulmonary arterial hypertension through PERK/eIF2α/NF-κB signaling. Chin J Physiol 65:187–198. https://doi.org/10.4103/0304-4920.354801

    Article  CAS  PubMed  Google Scholar 

  180. Wang AP, Li XH, Yang YM, Li WQ, Zhang W, Hu CP, Zhang Z, Li YJ (2015) A critical role of the mTOR/eIF2α pathway in hypoxia-induced pulmonary hypertension. PLoS ONE 10:e0130806. https://doi.org/10.1371/journal.pone.0130806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Pan Z, Wu X, Zhang X, Hu K (2023) Phosphodiesterase 4B activation exacerbates pulmonary hypertension induced by intermittent hypoxia by regulating mitochondrial injury and cAMP/PKA/p-CREB/PGC-1 alpha signaling. Biomed Pharmacother. https://doi.org/10.1016/j.biopha.2022.114095

    Article  PubMed  Google Scholar 

  182. Diebold L, Chandel NS (2016) Mitochondrial ROS regulation of proliferating cells. Free Radic Biol Med 100:86–93. https://doi.org/10.1016/j.freeradbiomed.2016.04.198

    Article  CAS  PubMed  Google Scholar 

  183. Korde AS, Yadav VR, Zheng YM, Wang YX (2011) Primary role of mitochondrial rieske iron-sulfur protein in hypoxic ROS production in pulmonary artery myocytes. Free Radic Biol Med 50:945–952. https://doi.org/10.1016/j.freeradbiomed.2011.01.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Sommer N, Alebrahimdehkordi N, Pak O, Knoepp F, Strielkov I, Scheibe S, Dufour E, Andjelković A, Sydykov A, Saraji A, Petrovic A, Quanz K, Hecker M, Kumar M, Wahl J, Kraut S, Seeger W, Schermuly RT, Ghofrani HA, Ramser K, Braun T, Jacobs HT, Weissmann N, Szibor M (2020) Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing. Sci Adv. https://doi.org/10.1126/sciadv.aba0694

    Article  PubMed  PubMed Central  Google Scholar 

  185. Sommer N, Hüttemann M, Pak O, Scheibe S, Knoepp F, Sinkler C, Malczyk M, Gierhardt M, Esfandiary A, Kraut S, Jonas F, Veith C, Aras S, Sydykov A, Alebrahimdehkordi N, Giehl K, Hecker M, Brandes RP, Seeger W, Grimminger F, Ghofrani HA, Schermuly RT, Grossman LI, Weissmann N (2017) Mitochondrial complex IV subunit 4 isoform 2 is essential for acute pulmonary oxygen sensing. Circ Res 121:424–438. https://doi.org/10.1161/circresaha.116.310482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Archer SL (2016) Acquired mitochondrial abnormalities, including epigenetic inhibition of superoxide dismutase 2, in pulmonary hypertension and cancer: therapeutic implications. Adv Exp Med Biol 903:29–53. https://doi.org/10.1007/978-1-4899-7678-9_3

    Article  CAS  PubMed  Google Scholar 

  187. Chen J, Zhang M, Liu Y, Zhao S, Wang Y, Wang M, Niu W, Jin F, Li Z (2023) Histone lactylation driven by mROS-mediated glycolytic shift promotes hypoxic pulmonary hypertension. J Mol Cell Biol. https://doi.org/10.1093/jmcb/mjac073

    Article  PubMed  PubMed Central  Google Scholar 

  188. Liu Y, Nie X, Zhu J, Wang T, Li Y, Wang Q, Sun Z (2021) NDUFA4L2 in smooth muscle promotes vascular remodeling in hypoxic pulmonary arterial hypertension. J Cell Mol Med 25:1221–1237. https://doi.org/10.1111/jcmm.16193

    Article  CAS  PubMed  Google Scholar 

  189. Kuhr FK, Smith KA, Song MY, Levitan I, Yuan JX (2012) New mechanisms of pulmonary arterial hypertension: role of Ca2+ signaling. Am J Physiol Heart Circ Physiol 302:H1546–H1562. https://doi.org/10.1152/ajpheart.00944.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Frazziano G, Moreno L, Moral-Sanz J, Menendez C, Escolano L, Gonzalez C, Villamor E, Alvarez-Sala JL, Cogolludo AL, Perez-Vizcaino F (2011) Neutral sphingomyelinase, NADPH oxidase and reactive oxygen species. Role in acute hypoxic pulmonary vasoconstriction. J Cell Physiol 226:2633–2640. https://doi.org/10.1002/jcp.22611

    Article  CAS  PubMed  Google Scholar 

  191. Veit F, Pak O, Brandes RP, Weissmann N (2015) Hypoxia-dependent reactive oxygen species signaling in the pulmonary circulation: focus on ion channels. Antioxid Redox Signal 22:537–552. https://doi.org/10.1089/ars.2014.6234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Golovina VA, Platoshyn O, Bailey CL, Wang J, Limsuwan A, Sweeney M, Rubin LJ, Yuan JX (2001) Upregulated TRP and enhanced capacitative Ca(2+) entry in human pulmonary artery myocytes during proliferation. Am J Physiol Heart Circ Physiol 280:H746–H755. https://doi.org/10.1152/ajpheart.2001.280.2.H746

    Article  CAS  PubMed  Google Scholar 

  193. Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, Olschewski A, Storch U, Mederos y Schnitzler M, Ghofrani HA, Schermuly RT (2006) Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Nat Acad Sci 103(50):19093–19098. https://doi.org/10.1073/pnas.0606728103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Rathore R, Zheng YM, Li XQ, Wang QS, Liu QH, Ginnan R, Singer HA, Ho YS, Wang YX (2006) Mitochondrial ROS-PKCepsilon signaling axis is uniquely involved in hypoxic increase in [Ca2+]i in pulmonary artery smooth muscle cells. Biochem Biophys Res Commun 351:784–790. https://doi.org/10.1016/j.bbrc.2006.10.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Lučić I, Truebestein L, Leonard TA (2016) Novel features of DAG-activated PKC isozymes reveal a conserved 3-D architecture. J Mol Biol 428:121–141. https://doi.org/10.1016/j.jmb.2015.11.001

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The study was supported by National Natural Science Foundation of China (Nos. 82070854) and the Natural Science Foundation of Shaanxi Province (2023-JC-YB 701).

Author information

Authors and Affiliations

  1. Faculty of Life Science & Medicine, Northwest University, Xi’an, 710127, Shaanxi, China

    Junming Zhang, Huimin Yan, Yan Wang, Xian Yue, Meng Wang, Limin Liu, Pengfei Qiao, Yixuan Zhu & Zhichao Li

Authors
  1. Junming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huimin Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xian Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Limin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pengfei Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yixuan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhichao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Junming Zhang wrote the manuscript. Huimin Yan, Yan Wang, Xian Yue and Meng Wang provided critical inputs during manuscript writing. Pengfei Qiao and Yixuan Zhu consulted relevant literature. Limin Liu and Zhichao Li revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhichao Li.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Yan, H., Wang, Y. et al. Emerging insights into pulmonary hypertension: the potential role of mitochondrial dysfunction and redox homeostasis. Mol Cell Biochem 480, 1407–1429 (2025). https://doi.org/10.1007/s11010-024-05096-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-024-05096-9

Keywords