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21 pages, 4846 KiB

Open AccessArticle

Mitochondrial HTRA2 Plays a Positive, Protective Role in Dictyostelium discoideum but Is Cytotoxic When Overexpressed

by Suwei Chen, Oana Sanislav, Sarah J. Annesley and Paul R. Fisher

Genes 2018, 9(7), 355; https://doi.org/10.3390/genes9070355 - 16 Jul 2018

Cited by 9 | Viewed by 4126

Abstract

HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson’s disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis [...] Read more.

HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson’s disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis in the mitochondrial intermembrane space. Its loss has been reported to result in accumulation of unfolded and misfolded proteins. However, in at least one case, PD-associated HTRA2 mutation can cause its hyperphosphorylation, possibly resulting in protease hyperactivity. The consequences of overactive mitochondrial HTRA2 are not clear. Dictyostelium discoideum provides a well-established model for studying mitochondrial dysfunction, such as has been implicated in the pathology of PD. We identified a single homologue of human HTRA2 encoded in the Dictyostelium discoideum genome and showed that it is localized to the mitochondria where it plays a cytoprotective role. Knockdown of HTRA2 expression caused defective morphogenesis in the multicellular phases of the Dictyostelium life cycle. In vegetative cells, it did not impair mitochondrial respiration but nonetheless caused slow growth (particularly when the cells were utilizing a bacterial food source), unaccompanied by significant defects in the requisite endocytic pathways. Despite its protective roles, we could not ectopically overexpress wild type HTRA2, suggesting that mitochondrial HTRA2 hyperactivity is lethal. This toxicity was abolished by replacing the essential catalytic serine S300 with alanine to ablate serine protease activity. Overexpression of protease-dead HTRA2 phenocopied the effects of knockdown, suggesting that the mutant protein competitively inhibits interactions between wild type HTRA2 and its binding partners. Our results show that cytopathological dysfunction can be caused either by too little or too much HTRA2 activity in the mitochondria and suggest that either could be a cause of PD. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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5712 KiB

Open AccessArticle

Proliferation Cycle Causes Age Dependent Mitochondrial Deficiencies and Contributes to the Aging of Stem Cells

by Qiuting Ren, Fan Zhang and Hong Xu

Genes 2017, 8(12), 397; https://doi.org/10.3390/genes8120397 - 19 Dec 2017

Cited by 4 | Viewed by 5249

Abstract

In addition to chronological aging, stem cells are also subject to proliferative aging during the adult life span. However, the consequences of proliferative cycle and their contributions to stem cells aging have not been well investigated. Using Drosophila female germ line stem cells [...] Read more.

In addition to chronological aging, stem cells are also subject to proliferative aging during the adult life span. However, the consequences of proliferative cycle and their contributions to stem cells aging have not been well investigated. Using Drosophila female germ line stem cells as a model, we found that the replication cycle leads to the age dependent decline of female fecundity, and is a major factor causing developmental abnormalities in the progeny of old females. The proliferative aging does not cause telomere shortening, but causes an accumulation of mitochondrial DNA (mtDNA) mutations or rearrangements at the control region. We propose that damaging mutations on mtDNA caused by accumulation of proliferation cycles in aged stem cells may disrupt mitochondrial respiration chain and impair mtDNA replication and represent a conserved mechanism underlying stem cell aging. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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Figure 1
Mitochondrial DNA (mtDNA) rearrangements and impaired mtDNA replication in ovaries of aged flies. (A) Schematic drawing of Drosophila melanogaster (Dm.) mtDNA. Enzyme sites of HindIII (H) and XhoI (X) are indicated. Sizes of digested fragments are also labelled. (B) Representative gel image of rolling cycle amplification of mtDNA (arrowhead) and DNA marker (M, kb). (C) Pattern of rolling cycle amplification (RCA) amplified mtDNA digested by XhoI and HindIII. The 5.8 kb fragment spanning the AT-rich region was recovered for restriction fragment length polymorphism (RFLP) analysis. (D) Schematic map of SspI site on 5.8 kb AT-rich region. (E) densitometry plot of SspI digestion pattern of 5.8 fragments spanning the AT-rich region from young (2-day-old) and old (60-day-old) ovaries, analyzed by Agilent Bioanalyzer 2100. Note the difference of bands (open arrowheads) demonstrating the rearrangements of AT-rich regions in aged ovaries. DNA dye standard (closed arrowheads) and DNA ladder are marked (M, bp). (F) Representative images showing 5-ethynyl-2’-deoxyuridine (EdU) incorporation into mtDNA (green puncta, arrowheads) in ovaries (dashed line, anterior toward left) from young (2-day-old) and old (40-day-old) female flies. Note that the number of EdU puncta was dramatically reduced in germarium from old fly. Arrowhead: mtDNA; arrow: nuclear DNA; scale bar: 10 µm. Full article ">Figure 2
Germline stem cell (GSC) proliferation cycle contributes to the age dependent decline of female fecundity and progeny’s fitness. (A,B). Representative images of germarium from 1-week-old mated (A) or virgin (B) female, stained with anti-VASA (green) for germ line cells and anti- phosphorylated histone H3 (P-H3, red) for mitotic cells. In mated flies, dividing GSC (arrowhead) and germ cell cysts (arrows) are present. Scale bar: 10 µm. (C) Quantification of mitotic germ cells in germaria of mated and virgin female flies. No. (#) of mitotic germ cells flies is significantly less in virgin than mated flies (n = 100 germaria, p < 0.001). We also counted the P-H3 positive GSCs. There were 13 dividing GSCs in total from 100 germaria of mated female flies, but only four out of 100 virgin females. (D) Female fecundity was assayed by calculating the average egg production per female per day over 40 days. (E) Egg hatching rates plotted over maternal age. Black line, mated female flies; red line, female flies maintained as virgins for two weeks after eclosion. A total of 150 female flies were used for each group in (D,E). Each group was assayed in 30 vials with five female flies in each vial. Arrowhead, time point when virgin flies were mated with males. Full article ">Figure 3
Aging does not lead to telomere shortening in GSCs. (A) Total DNA from the ovaries of young (2-day-old) and old (60-day-old) females were prepared and the copy numbers of three telomeric transposons Het-A, TARAE and TART-A1 were determined by real time PCR and plotted (n = 3). A non-telomeric transposon Joecy was used as an internal control. (B) Quantifications of telomere (tel.) DNA contents by normalizing fluorescence in situ hybridization (FISH) signal of telomere DNA with FISH signal of his4 locus in GSCs of young and old females. No significant difference between young and old GSCs (n = 100 for each group). (C,D) Representative images of two color FISH against telomere DNA (green, mix of three probes against all three telomeric transposons) and his4 locus (red) in young ((C), 2-day-old) and old ((D), 60-day-old) germaria. Box regions were enlarged for better illustrations of telomere DNA (arrowheads) and his4 locus (arrows). Scale bar: 5 µm. Full article ">Figure 4
Aged GSCs have increased mtDNA mutation loads and defective electron transport chain complexes. (A) Cross scheme to assay the influence of maternal age (F0) on mtDNA mutation frequency in progeny (F1), as an indication of mtDNA mutation loads in F0 GSCs. (B) The different groups of F1 females expressing mitoXhoI in germ cells (UASp-MitoXhoI/+; nanos-gal4/+, n > 100) were produced by the same group of F0 females (nanos-gal4) at different ages. The frequency of fertile F1 females, as an indication of mtDNA mutation frequency in F0 GSCs is plotted against age of F0 females. The positive correlation between the number of fertile F1 females and the age of F0 females suggests that there were more mtDNA mutations in older GSCs in F0 females. (C) Ovaries of young (2-day-old) or old (60-day-old) females that were either mated with males or maintained as virgins were stained for dual succinate dehydrogenase and cytochrome C oxidase (COX) activity. The representative images and their percentage (n = 20) for each group are shown. Nearly 100% of ovaries of young mated females, young virgins and old virgins displayed normal COX activity (brown color). Note that the anterior part of the germarium (boxed and enlarged view), the location of stem cells and early stage cysts are nearly colorless, showing that mitochondria are mostly inactive in this developmental stage. In addition, 55% of ovaries from old mated females were completely lacking in COX activity (blue color). Forty percent of ovaries from old mated flies (inserted panel) showed a mosaic pattern of normal and deficient COX activity (arrowheads), suggesting that COX is normal in one germ line stem cell, but disrupted in another one in the same ovariole. Full article ">

Review

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19 pages, 2457 KiB

Open AccessReview

Influence of Maternal Aging on Mitochondrial Heterogeneity, Inheritance, and Function in Oocytes and Preimplantation Embryos

by Dori C. Woods, Konstantin Khrapko and Jonathan L. Tilly

Genes 2018, 9(5), 265; https://doi.org/10.3390/genes9050265 - 21 May 2018

Cited by 38 | Viewed by 7620

Abstract

Contrasting the equal contribution of nuclear genetic material from maternal and paternal sources to offspring, passage of mitochondria, and thus mitochondrial DNA (mtDNA), is uniparental through the egg. Since mitochondria in eggs are ancestral to all somatic mitochondria of the next generation and [...] Read more.

Contrasting the equal contribution of nuclear genetic material from maternal and paternal sources to offspring, passage of mitochondria, and thus mitochondrial DNA (mtDNA), is uniparental through the egg. Since mitochondria in eggs are ancestral to all somatic mitochondria of the next generation and to all cells of future generations, oocytes must prepare for the high energetic demands of maturation, fertilization and embryogenesis while simultaneously ensuring that their mitochondrial genomes are inherited in an undamaged state. Although significant effort has been made to understand how the mtDNA bottleneck and purifying selection act coordinately to prevent silent and unchecked spreading of invisible mtDNA mutations through the female germ line across successive generations, it is unknown if and how somatic cells of the immediate next generation are spared from inheritance of detrimental mtDNA molecules. Here, we review unique aspects of mitochondrial activity and segregation in eggs and early embryos, and how these events play into embryonic developmental competency in the face of advancing maternal age. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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Figure 1
Confocal photomicrographs of mitochondrial distribution patterns in mouse oocytes. Oocytes collected from adult female mice following hormone stimulation-induced superovulation were classified as metaphase-II (extruded first polar body), and then incubated with MitoTracker Red (Thermo Fisher Scientific, Waltham, MA). Oocytes were immediately coverslipped and imaged using a Zeiss laser scanning confocal microscope. Mitochondria are noticeably punctate and present throughout the oocyte. Examples demonstrate multiple focal planes, with perinuclear distribution (indicated by white asterisk), and a polar body (p) is visible in the top right panel. Scale bar = 15 μm. Full article ">Figure 2
Mitochondrial ultrastructural features, as determined by transmission electron microscopy, in primary-stage oocytes contained within follicles of reproductive-age human ovaries: (A) Mitochondria are localized as clusters (mitochondrial clusters; mc) within oocytes. The oocyte-granulosa cell interface (i) is also depicted, and demonstrates areas of interdigitation between the oocyte and surrounding granulosa cells. Scale bar = 200 µm. (B,C) Mitochondrial morphology (m) depicted at two magnifications reveals that most mitochondria exhibit an ovoid morphology, dense matrices, and few cristae. However, a large variation in mitochondrial size can be observed, along with multiple examples of mitochondria that fall outside of the characteristic morphology described above. Tissues were collected and prepared for TEM by non-coagulative aldehyde fixation, followed by sectioning on an ultramicrotome. Images were acquired using a JEOL JEM-1010 transmission electron microscope. Full article ">

9 pages, 223 KiB

Open AccessReview

Brain Mitochondria, Aging, and Parkinson’s Disease

by Mario Rango and Nereo Bresolin

Genes 2018, 9(5), 250; https://doi.org/10.3390/genes9050250 - 11 May 2018

Cited by 61 | Viewed by 6847

Abstract

This paper reconsiders the role of mitochondria in aging and in Parkinson’s Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered [...] Read more.

This paper reconsiders the role of mitochondria in aging and in Parkinson’s Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation. Many of these mitochondrial alterations are also found in the PD brain specifically in the substantia nigra (SN). mtDNA deletions and development of respiratory chain deficiency in SN neurons of aged individuals as well as of individuals with PD converge towards a shared pathway, which leads to neuronal dysfunction and death. Finally, several nuclear genes that are mutated in hereditary PD are usually implicated in mitochondrial functioning to a various extent and their mutation may cause mitochondrial impairment. In conclusion, a tight link exists between mitochondria, aging, and PD. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

12 pages, 5971 KiB

Open AccessReview

Roles of Mitochondrial DNA Mutations in Stem Cell Ageing

by Tianhong Su, Doug M. Turnbull and Laura C. Greaves

Genes 2018, 9(4), 182; https://doi.org/10.3390/genes9040182 - 27 Mar 2018

Cited by 16 | Viewed by 9341

Abstract

Mitochondrial DNA (mtDNA) mutations accumulate in somatic stem cells during ageing and cause mitochondrial dysfunction. In this review, we summarize the studies that link mtDNA mutations to stem cell ageing. We discuss the age-related behaviours of the somatic mtDNA mutations in stem cell [...] Read more.

Mitochondrial DNA (mtDNA) mutations accumulate in somatic stem cells during ageing and cause mitochondrial dysfunction. In this review, we summarize the studies that link mtDNA mutations to stem cell ageing. We discuss the age-related behaviours of the somatic mtDNA mutations in stem cell populations and how they potentially contribute to stem cell ageing by altering mitochondrial properties in humans and in mtDNA-mutator mice. We also draw attention to the diverse fates of the mtDNA mutations with different origins during ageing, with potential selective pressures on the germline inherited but not the somatic mtDNA mutations. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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Figure 1
Immunofluorescence images of the respiratory chain deficiency caused by the age-dependent accumulation of somatic mitochondrial DNA (mtDNA) mutations in the colon. Respiratory chain complex IV (marked by the COX1 antibody) is encoded by both mtDNA and nuclear DNA (nDNA), which is affected by the increased burden of mtDNA mutations. Complex II (labelled by the SDHA antibody) is entirely encoded by nDNA. The complex IV deficient colonic cells are indicated red in the merged picture. COX1, a key subunit of complex IV encoded by mtDNA. SDHA, one of the four nuclear encoded subunits of complex II. Scale bar: 50 µm. Full article ">Figure 2
Schematic diagram of how the mitochondrial abnormalities caused by the age-dependent accumulation of somatic mtDNA mutations affect stem cell homeostasis in the mtDNA mutator mice. Mitochondrial DNA mutagenesis causes minor changes in reactive oxygen species (ROS)/redox level, which may alter stem cell identity (quiescence and regeneration). The somatic mtDNA mutation increases apoptosis and also shifts the level of mitophagy/autophagy in the stem cell population possibly through the loss of the mitochondrial membrane potential (MMP), which may eventually engender stem cell/progenitor depletion and accelerate stem cell senescence. Mitochondrial DNA mutagenesis imbalances mitochondrial dynamics towards fission independent of ATP production, which can affect stem cell self-renewal and differentiation. The amassing of somatic mtDNA mutations prevents stem cells from converting glycolysis to oxidative phosphorylation (OXPHOS) as they differentiate, resulting in cell death and failure to produce progenies. Normal mitochondria are coloured orange and dysfunctional mitochondria are in blue. Mutated mtDNA are red and the normal mtDNA are blue. Full article ">

13 pages, 1531 KiB

Open AccessFeature PaperReview

Is There Still Any Role for Oxidative Stress in Mitochondrial DNA-Dependent Aging?

by Gábor Zsurka, Viktoriya Peeva, Alexander Kotlyar and Wolfram S. Kunz

Genes 2018, 9(4), 175; https://doi.org/10.3390/genes9040175 - 21 Mar 2018

Cited by 46 | Viewed by 6533

Abstract

Recent deep sequencing data has provided compelling evidence that the spectrum of somatic point mutations in mitochondrial DNA (mtDNA) in aging tissues lacks G > T transversion mutations. This fact cannot, however, be used as an argument for the missing contribution of reactive [...] Read more.

Recent deep sequencing data has provided compelling evidence that the spectrum of somatic point mutations in mitochondrial DNA (mtDNA) in aging tissues lacks G > T transversion mutations. This fact cannot, however, be used as an argument for the missing contribution of reactive oxygen species (ROS) to mitochondria-related aging because it is probably caused by the nucleotide selectivity of mitochondrial DNA polymerase ? (POLG). In contrast to point mutations, the age-dependent accumulation of mitochondrial DNA deletions is, in light of recent experimental data, still explainable by the segregation of mutant molecules generated by the direct mutagenic effects of ROS (in particular, of HO· radicals formed from H₂O₂ by a Fenton reaction). The source of ROS remains controversial, because the mitochondrial contribution to tissue ROS production is probably lower than previously thought. Importantly, in the discussion about the potential role of oxidative stress in mitochondria-dependent aging, ROS generated by inflammation-linked processes and the distribution of free iron also require careful consideration. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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20 pages, 615 KiB

Open AccessReview

Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction

by Corina T. Madreiter-Sokolowski, Armin A. Sokolowski, Markus Waldeck-Weiermair, Roland Malli and Wolfgang F. Graier

Genes 2018, 9(3), 165; https://doi.org/10.3390/genes9030165 - 16 Mar 2018

Cited by 43 | Viewed by 10649

Abstract

Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca²⁺ sequestration, fine-tuning [...] Read more.

Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca²⁺ sequestration, fine-tuning mitochondrial activity appropriately, is a tightrope walk during aging. For instance, the mitochondrial oxidative phosphorylation (OXPHOS) ensures a supply of adenosine triphosphate (ATP), but is also the main source of potentially harmful levels of reactive oxygen species (ROS). Moreover, mitochondrial function is strongly linked to mitochondrial Ca²⁺ homeostasis and mitochondrial shape, which undergo various alterations during aging. Since mitochondria play such a critical role in an organism’s process of aging, they also offer promising targets for manipulation of senescent cellular functions. Accordingly, interventions delaying the onset of age-associated disorders involve the manipulation of mitochondrial function, including caloric restriction (CR) or exercise, as well as drugs, such as metformin, aspirin, and polyphenols. In this review, we discuss mitochondria’s role in and impact on cellular aging and their potential to serve as a target for therapeutic interventions against age-related cellular dysfunction. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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13 pages, 444 KiB

Open AccessReview

The Aging Mitochondria

by Pierre Theurey and Paola Pizzo

Genes 2018, 9(1), 22; https://doi.org/10.3390/genes9010022 - 9 Jan 2018

Cited by 74 | Viewed by 21994

Abstract

Mitochondrial dysfunction is a central event in many pathologies and contributes as well to age-related processes. However, distinguishing between primary mitochondrial dysfunction driving aging and a secondary mitochondrial impairment resulting from other cell alterations remains challenging. Indeed, even though mitochondria undeniably play a [...] Read more.

Mitochondrial dysfunction is a central event in many pathologies and contributes as well to age-related processes. However, distinguishing between primary mitochondrial dysfunction driving aging and a secondary mitochondrial impairment resulting from other cell alterations remains challenging. Indeed, even though mitochondria undeniably play a crucial role in aging pathways at the cellular and organismal level, the original hypothesis in which mitochondrial dysfunction and production of free radicals represent the main driving force of cell degeneration has been strongly challenged. In this review, we will first describe mitochondrial dysfunctions observed in aged tissue, and how these features have been linked to mitochondrial reactive oxygen species (ROS)–mediated cell damage and mitochondrial DNA (mtDNA) mutations. We will also discuss the clues that led to consider mitochondria as the starting point in the aging process, and how recent research has showed that the mitochondria aging axis represents instead a more complex and multifactorial signaling pathway. New working hypothesis will be also presented in which mitochondria are considered at the center of a complex web of cell dysfunctions that eventually leads to cell senescence and death. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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1141 KiB

Open AccessReview

The Mitochondrial Basis of Aging and Age-Related Disorders

by Sarika Srivastava

Genes 2017, 8(12), 398; https://doi.org/10.3390/genes8120398 - 19 Dec 2017

Cited by 260 | Viewed by 24711

Abstract

Aging is a natural phenomenon characterized by progressive decline in tissue and organ function leading to increased risk of disease and mortality. Among diverse factors that contribute to human aging, the mitochondrial dysfunction has emerged as one of the key hallmarks of aging [...] Read more.

Aging is a natural phenomenon characterized by progressive decline in tissue and organ function leading to increased risk of disease and mortality. Among diverse factors that contribute to human aging, the mitochondrial dysfunction has emerged as one of the key hallmarks of aging process and is linked to the development of numerous age-related pathologies including metabolic syndrome, neurodegenerative disorders, cardiovascular diseases and cancer. Mitochondria are central in the regulation of energy and metabolic homeostasis, and harbor a complex quality control system that limits mitochondrial damage to ensure mitochondrial integrity and function. The intricate regulatory network that balances the generation of new and removal of damaged mitochondria forms the basis of aging and longevity. Here, I will review our current understanding on how mitochondrial functional decline contributes to aging, including the role of somatic mitochondrial DNA (mtDNA) mutations, reactive oxygen species (ROS), mitochondrial dynamics and quality control pathways. I will further discuss the emerging evidence on how dysregulated mitochondrial dynamics, mitochondrial biogenesis and turnover mechanisms contribute to the pathogenesis of age-related disorders. Strategies aimed to enhance mitochondrial function by targeting mitochondrial dynamics, quality control, and mitohormesis pathways might promote healthy aging, protect against age-related diseases, and mediate longevity. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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530 KiB

Open AccessReview

Mitochondria and ?-Synuclein: Friends or Foes in the Pathogenesis of Parkinson’s Disease?

by Gaia Faustini, Federica Bono, Alessandra Valerio, Marina Pizzi, PierFranco Spano and Arianna Bellucci

Genes 2017, 8(12), 377; https://doi.org/10.3390/genes8120377 - 8 Dec 2017

Cited by 53 | Viewed by 7923

Abstract

Parkinson’s disease (PD) is a movement disorder characterized by dopaminergic nigrostriatal neuron degeneration and the formation of Lewy bodies (LB), pathological inclusions containing fibrils that are mainly composed of ?-synuclein. Dopaminergic neurons, for their intrinsic characteristics, have a high energy demand that relies [...] Read more.

Parkinson’s disease (PD) is a movement disorder characterized by dopaminergic nigrostriatal neuron degeneration and the formation of Lewy bodies (LB), pathological inclusions containing fibrils that are mainly composed of ?-synuclein. Dopaminergic neurons, for their intrinsic characteristics, have a high energy demand that relies on the efficiency of the mitochondria respiratory chain. Dysregulations of mitochondria, deriving from alterations of complex I protein or oxidative DNA damage, change the trafficking, size and morphology of these organelles. Of note, these mitochondrial bioenergetics defects have been related to PD. A series of experimental evidence supports that ?-synuclein physiological action is relevant for mitochondrial homeostasis, while its pathological aggregation can negatively impinge on mitochondrial function. It thus appears that imbalances in the equilibrium between the reciprocal modulatory action of mitochondria and ?-synuclein can contribute to PD onset by inducing neuronal impairment. This review will try to highlight the role of physiological and pathological ?-synuclein in the modulation of mitochondrial functions. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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Other

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12 pages, 1243 KiB

Open AccessPerspective

Resolving the Enigma of the Clonal Expansion of mtDNA Deletions

by Axel Kowald and Thomas B.L. Kirkwood

Genes 2018, 9(3), 126; https://doi.org/10.3390/genes9030126 - 27 Feb 2018

Cited by 29 | Viewed by 5497

Abstract

Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an [...] Read more.

Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an important role during aging. In both cases, point mutations or large deletions accumulate inside cells, leading to functional impairment once a certain threshold has been surpassed. In most cases, it is a single type of mutant that clonally expands and out-competes the wild type mtDNA, with different mutant molecules being amplified in different cells. The challenge is to explain where the selection advantage for the accumulation comes from, why such a large range of different deletions seem to possess this advantage, and how this process can scale to species with different lifespans such as those of rats and man. From this perspective, we provide an overview of current ideas, present an update of our own proposal, and discuss the wider relevance of the phenomenon for aging. Full article

(This article belongs to the Special Issue Mitochondria and Aging)

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