Mitochondrial Dynamics: Mechanisms and Pathologies


Mitochondrial dynamics, a cellular process describing continuous change of shape and location of mitochondria, has drawn much attention recently due to its involvement in cell injury and human pathologies. Mitochondrial fission and fusion are the major processes that alter mitochondrial morphology. Molecular machineries for mitochondrial fission and fusion include proteins of dynamin family large GTPases that remodel biological membranes. Mutations in these proteins cause hereditary diseases or death in human, indicating that mitochondrial fission and fusion are important cellular processes. Identification of additional factors participating in mitochondrial fission and fusion still continues. Recent studies demonstrate that mitochondrial fission/fusion process is under tight regulation through cellular signalling networks and functional states of mitochondria. This information suggests that cellular cues both extrinsic and intrinsic to mitochondria regulate mitochondrial fission and fusion, indicating an important role of mitochondrial fission and fusion in controlling mitochondrial functionality. Many additional pathologies are associated with aberrant mitochondrial fission and fusion, and defining the form–function relationship of mitochondria will be the key for understanding disease aetiology and therapeutic application.

Key Concepts:

  • Mitochondria take a variety of shapes depending on cell types and activities.

  • Fission and fusion of mitochondria are the main processes changing their morphology.

  • Dynamin‐related proteins (DRPs) remodel mitochondrial membranes for fission and fusion.

  • Additional proteins and factors including signal‐induced protein modifications participate in mitochondrial fission and fusion.

  • Mutations in genes in mitochondrial fission and fusion are detrimental to human health.

  • Many diseases such as neurodegeneration, metabolic diseases, ischemia‐reperfusion injury, heart diseases, and aging are directly and indirectly associated with dysregulation of mitochondrial fission and fusion.

Keywords: mitochondria; mitochondrial dynamics; fission; fusion; dynamin; dynamin‐related proteins; apoptosis; pathology; neurodegeneration

Figure 1.

Mitochondrial morphology in Clone 9, a cell line derived from rat liver (a), and in rat cardiomyocyte (b, c). Filamentous tubules are the major mitochondrial morphology in cultured cell line. Inset in (a) shows elongated tubular mitochondria in cultured cells. On the other hand, both light (b) and electron (c) micrographs show globular mitochondria tightly packed along the myofibrils in cardiomyocytes.

Figure 2.

Molecular structure of DRPs. The dynamin core domains GTPase, Middle, and GED are found in DLP1 and OPA1 whereas the presence of the Middle domain and GED is unclear in Mfn1 and 2. Arrowheads in the OPA1 indicate proteolytic cleavage sites. DLP1, dynamin‐like protein 1; Mfn1/2, mitofusin 1 and 2; OPA1, optic atrophy1; PHD, pleckstrin homology domain; GED, GTPase effector domain; PRD, proline‐rich domain; HR1, heptad‐repeat 1; HR2, heptad‐repeat 2; TM, transmembrane; MTS, mitochondrial targeting sequence; CC, coiled coil domain; MPP, mitochondrial processing peptidase.

Figure 3.

Mitochondrial fission. The ER is suggested to mark the fission site where DLP1 forms helical rings for GTP hydrolysis‐mediated scission of the mitochondrial tubule. DLP1 translocation from the cytosol to the mitochondrial surface is facilitated by Mff, Fis1, or MIEF1 (MiD49/51).

Figure 4.

Mitochondrial fusion. Mfn tethers and fuses the outer membranes (OMM) of adjacent mitochondria. Following the OMM fusion, OPA1 mediates fusion of the inner membranes (IMM).



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Further Reading

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Lee, Hakjoo, and Yoon, Yisang(Jun 2012) Mitochondrial Dynamics: Mechanisms and Pathologies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021867]