Abstract
Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated.
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Acknowledgements
This work was supported by the Medical Research Council (MC_UU_00028/5) and Biotechnology and Biological Sciences Research Council (BBSRC) (BB/W008467/1). The original, author-provided figures were prepared with the paid version of BioRender and re-drawn by the journal.
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Glossary
- Actin nucleation
-
The process by which actin monomers are transformed into actin filaments. The process requires the action of different protein scaffold complexes, including the actin-related protein 2 (ARP2)–ARP3 complex and its activator, the Wiskott–Aldrich syndrome protein and Scar homologue (WASH) complex, which drive actin branching.
- Apoptosis
-
A programmed cell death process essential for the removal of damaged cells during development and disease. It can be activated by the cytosolic leakage of mitochondrial damage-associated molecular patterns (DAMPs), ultimately leading to caspase activation and the degradation of cellular components.
- Autophagy
-
A highly conserved intracellular process in eukaryotes that mediates the bulk degradation and recycling of cytoplasmatic materials by delivering them into lysosomes.
- Chromobodies
-
Engineered small functional antibodies fused to a fluorescent protein, designed to recognize specific intracellular targets and allow for the analysis of target dynamics by microscopy.
- Endoplasmic reticulum
-
(ER). The largest organelle in the cell, which serves multiple functions including protein and lipid synthesis. The ER can be classified as rough ER, characterized by the presence of ribosomes, and smooth ER, devoid of ribosomes. ER is formed by three major subdomains: nuclear envelope (NE), the juxtanuclear area (characterized by the presence of expanded ER sheets) and the peripheral area, enriched in tubular structures.
- FtsZ
-
A highly conserved GTPase found in most of bacterial groups and considered the major cytoskeletal prokaryotic protein. FtsZ assembles in ring-like structures at the division site to drive bacterial cytokinesis.
- Glycolytic conditions
-
A metabolic state wherein glycolysis is the main pathway for energy production, which involves a series of enzymatic reactions that break down glucose into pyruvate, resulting in the generation of ATP and the production of NADH.
- Helical bundle
-
Protein folded structure formed by the packaging of multiple α-helices, which create a hydrophobic core in the centre.
- Hydrogenosomes
-
Membrane-bound organelles present in some anaerobic microorganisms thought to have evolved from protomitochondria to generate molecular hydrogen and ATP.
- Krebs cycle
-
Also known as citric acid cycle, it is an amphibolic pathway taking place in the mitochondrial matrix wherein one acetyl-coA molecule gives rise to two molecules of CO2, resulting in the generation of one molecule of GTP, three molecules of reduced form of NADH and one molecule of reduced FADH2.
- Large GTPases
-
Like other GTPases, large GTPases hydrolyse GTP into GDP (guanosine diphosphate) and inorganic phosphate. Compared to small GTPases, large GTPases have higher intrinsic GTPase activity, which is stimulated by the nucleotide-dependent dimerization of the G domain.
- Membrane contact sites
-
Regions wherein the membranes of two or more organelles are closely apposed (10–30-nm distance) but do not fuse with each other, creating a signalling platform that allows exchange and communication between organelles.
- Membrane hemifusion
-
A partial fusion state wherein the two outer, but not inner, membrane leaflets undergo a reversible fusion event.
- Mitochondrial DNA
-
(mtDNA). The human mitochondrial genome is a 16.6-kb circle of double-stranded DNA that harbours 37 genes encoding two ribosomal RNAs (rRNAs), 22 tRNAs and 13 polypeptides, essential for oxidative phosphorylation (OXPHOS).
- Mitophagy
-
The selective degradation of small mitochondria within autophagosomal structures. This process is primarily mediated by the ubiquitination of damaged mitochondria or by the recruitment of the autophagic machinery through different receptors on the mitochondrial membranes.
- Nucleoid
-
DNA–protein complex in the mitochondrial matrix that package mtDNA into compacted structures. Every nucleoid contains 1.4 mtDNA molecules and the degree of compaction regulates mtDNA accessibility and expression.
- Power strokes
-
Mechanical processes fuelled by GTP hydrolysis, which involves conformational re-arrangements of the helical rings formed by dynamin superfamily proteins, ultimately leading to membrane constriction.
- Stalk domain
-
In structural biology, an aminoacidic region that connects two distant regions of the protein.
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Tábara, LC., Segawa, M. & Prudent, J. Molecular mechanisms of mitochondrial dynamics. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00785-1
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DOI: https://doi.org/10.1038/s41580-024-00785-1
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