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  • Review Article
  • Published:

Disturbed mitochondrial dynamics and neurodegenerative disorders

Key Points

  • Mitochondria do not exist as isolated organelles; instead, they form a highly interconnected tubular network throughout the cell

  • The state of this dynamic mitochondrial network under both physiological and disease conditions is dictated by the balance between mitochondrial pro-fusion and pro-fission forces

  • Optic atrophy protein 1 (OPA1) and mitofusin 2 (MFN2) are two important protein mediators of mitochondrial fusion

  • Pathogenic OPA1 and MFN2 mutations cause autosomal dominant optic atrophy and axonal Charcot–Marie–Tooth disease type 2A, respectively

  • Mounting evidence implicates disturbed mitochondrial dynamics in the pathogenesis of complex neurodegenerative disorders such as Alzheimer disease, Parkinson disease and Huntington disease

  • Although treatment options for disorders of mitochondrial dynamics are currently limited, the future looks promising for the development of novel neuroprotective strategies and innovative gene therapy approaches

Abstract

Mitochondria form a highly interconnected tubular network throughout the cell via a dynamic process, with mitochondrial segments fusing and breaking apart continuously. Strong evidence has emerged to implicate disturbed mitochondrial fusion and fission as central pathological components underpinning a number of childhood and adult-onset neurodegenerative disorders. Several proteins that regulate the morphology of the mitochondrial network have been identified, the most widely studied of which are optic atrophy 1 and mitofusin 2. Pathogenic mutations that disrupt these two pro-fusion proteins cause autosomal dominant optic atrophy and axonal Charcot–Marie–Tooth disease type 2A, respectively. These disorders predominantly affect specialized neurons that require precise shuttling of mitochondria over long axonal distances. Considerable insight has also been gained by carefully dissecting the deleterious consequences of imbalances in mitochondrial fusion and fission on respiratory chain function, mitochondrial quality control (mitophagy), and programmed cell death. Interestingly, these cellular processes are also implicated in more-common complex neurodegenerative disorders, such as Alzheimer disease and Parkinson disease, indicating a common pathological thread and a close relationship with mitochondrial structure, function and localization. Understanding how these fundamental processes become disrupted will prove crucial to the development of therapies for the growing number of neurodegenerative disorders linked to disturbed mitochondrial dynamics.

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Figure 1: Mitochondrial dynamics and interactions.
Figure 2: Mitochondrial network fragmentation in OPA1-mutant fibroblasts.
Figure 3: Major pathways implicated in neurodegenerative disorders.
Figure 4: DOA+ phenotype and mtDNA instability.

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Acknowledgements

P.Y.-W.-M. is a Medical Research Council (MRC, UK) Clinician Scientist. He also receives funding from Fight for Sight (UK) and the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration. V.C. is supported by Telethon-Italy grants GPP1005, GGP06233 and GGP11182. P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science and a UK NIHR Senior Investigator who also receives funding from the MRC and the NIHR Biomedical Research Centre for Ageing and Age-Related Disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust.

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F.B. and P.Y.-W.-M. researched data for and wrote the article. All the authors provided substantial contributions to the discussion of content and to editing the manuscript before submission.

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Correspondence to Patrick Yu-Wai-Man.

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Burté, F., Carelli, V., Chinnery, P. et al. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol 11, 11–24 (2015). https://doi.org/10.1038/nrneurol.2014.228

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