Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 18 (R2), R169-76

Mitochondrial Dynamics--Fusion, Fission, Movement, and Mitophagy--In Neurodegenerative Diseases

Affiliations
Review

Mitochondrial Dynamics--Fusion, Fission, Movement, and Mitophagy--In Neurodegenerative Diseases

Hsiuchen Chen et al. Hum Mol Genet.

Abstract

Neurons are metabolically active cells with high energy demands at locations distant from the cell body. As a result, these cells are particularly dependent on mitochondrial function, as reflected by the observation that diseases of mitochondrial dysfunction often have a neurodegenerative component. Recent discoveries have highlighted that neurons are reliant particularly on the dynamic properties of mitochondria. Mitochondria are dynamic organelles by several criteria. They engage in repeated cycles of fusion and fission, which serve to intermix the lipids and contents of a population of mitochondria. In addition, mitochondria are actively recruited to subcellular sites, such as the axonal and dendritic processes of neurons. Finally, the quality of a mitochondrial population is maintained through mitophagy, a form of autophagy in which defective mitochondria are selectively degraded. We review the general features of mitochondrial dynamics, incorporating recent findings on mitochondrial fusion, fission, transport and mitophagy. Defects in these key features are associated with neurodegenerative disease. Charcot-Marie-Tooth type 2A, a peripheral neuropathy, and dominant optic atrophy, an inherited optic neuropathy, result from a primary deficiency of mitochondrial fusion. Moreover, several major neurodegenerative diseases--including Parkinson's, Alzheimer's and Huntington's disease--involve disruption of mitochondrial dynamics. Remarkably, in several disease models, the manipulation of mitochondrial fusion or fission can partially rescue disease phenotypes. We review how mitochondrial dynamics is altered in these neurodegenerative diseases and discuss the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy.

Figures

Figure 1.
Figure 1.
Defects in mitochondrial dynamics that lead to neuronal dysfunction. (A) In wild-type neurons, mitochondria travel long distances from the cell body out to dendritic and axonal termini, where they play important roles in ATP production and calcium homeostasis. (B) In the absence of fusion, the mitochondrial population fragments and a subset show ultrastructural defects and dysfunction (red). The mitochondria secondarily have transport defects that prevent proper distribution to the periphery. (C) In the absence of fission, the mitochondrial population is excessively long and interconnected, and a subset shows dysfunction (red). These large mitochondria cluster within the cell body and are not efficiently transported to the periphery. (D) Primary defects in mitochondrial motility prevent distribution of mitochondria to the periphery. (E) In the absence of mitophagy, abnormal mitochondria (red) accumulate.
Figure 2.
Figure 2.
Neurodegenerative disease associated with defects in mitochondrial dynamics. Neuronal systems affected in neurodegenerative disease are shown. For each disease, only the primary affected regions are indicated, but there is evidence for more widespread involvement.

Similar articles

See all similar articles

Cited by 489 PubMed Central articles

See all "Cited by" articles

References

    1. Detmer S.A., Chan D.C. Functions and dysfunctions of mitochondrial dynamics. Nat. Rev. Mol. Cell Biol. 2007;8:870–879. - PubMed
    1. Okamoto K., Shaw J.M. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu. Rev. Genet. 2005;39:503–536. - PubMed
    1. Meeusen S., DeVay R., Block J., Cassidy-Stone A., Wayson S., McCaffery J.M., Nunnari J. Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell. 2006;127:383–395. - PubMed
    1. Song Z., Ghochani M., McCaffery J.M., Frey T.G., Chan D.C. Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion. Mol. Biol. Cell. 2009 May 28 [Epub ahead of print] - PMC - PubMed
    1. Alavi M.V., Bette S., Schimpf S., Schuettauf F., Schraermeyer U., Wehrl H.F., Ruttiger L., Beck S.C., Tonagel F., Pichler B.J., et al. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain. 2007;130:1029–1042. - PubMed

Publication types

Feedback