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Dysregulation of mitochondrial fusion and fission: an emerging concept in neurodegeneration

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Abstract

Mitochondrial dysfunction is increasingly being recognized as an important factor contributing to the pathogenesis of neurodegenerative disorders. However, at present, the molecular basis underlying the decline in mitochondrial function is not really understood, but recent experimental evidence has shed some light on the pivotal role of mitochondrial morphology control in this process. In particular, dysregulated mitochondrial fusion and fission events can now be regarded as playing important pathogenic roles in neurodegeneration. In healthy cells, mitochondrial morphology is maintained through a dynamic balance between fusion and fission processes, and this regulated balance seems to be required for maintaining normal mitochondrial and cellular function. Moreover, during programmed cell death, activation of mitochondrial fission occurs, leading to mitochondrial fragmentation (Karbowski et al. in J Cell Biol 164:493–499, 2004). Consequently, inhibition of mitochondrial fission results in a significantly reduced cellular susceptibility toward apoptosis. The clinical relevance of maintaining a finely tuned balance between mitochondrial fusion and fission processes is underscored by the fact that the pathogenesis of certain hereditary neurodegenerative disorders such as autosomal dominant optic atrophy (ADOA) and Charcot-Marie-Tooth neuropathy type 2A (CMT2A) can now be linked to mutations in genes encoding mediators of mitochondrial fusion. In this article, I will summarize important aspects of what is currently known about the molecular machinery regulating mitochondrial fission and fusion in mammalian cells. Special emphasis will be given to the consequences of dysregulated mitochondrial morphology with regard to the pathogenesis of neurodegenerative disorders. A detailed understanding of the mitochondrial fission and fusion machinery will be a prerequisite for the development of therapeutic approaches to inhibit the neuronal cell death underlying certain neurodegenerative disorders.

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Abbreviations

ADOA:

Autosomal dominant optic atrophy

CMT2A:

Charcot-Marie-Tooth neuropathy, type 2A

Drp1:

Dynamin-related protein1

Fzo:

Fuzzy onions

IMM:

Inner mitochondrial membrane

IMS:

Intermembrane space

Mgm1p:

Mitochondrial genome maintenance1

Mfn:

Mitofusin

mtDNA:

Mitochondrial DNA

OMM:

Outer mitochondrial membrane

OPA:

Optic atrophy

Rbd1p:

Rhomboid-1

STS:

Staurosporine

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Acknowledgments

I would like to thank T. Pietsch and A. Santel for critical reading and helpful suggestions on the manuscript.

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  1. Department of Neuropathology, Bonn University Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Stephan Frank

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Frank, S. Dysregulation of mitochondrial fusion and fission: an emerging concept in neurodegeneration. Acta Neuropathol 111, 93–100 (2006). https://doi.org/10.1007/s00401-005-0002-3

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