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Role of the Mitochondrial Fission Protein Drp1 in Synaptic Damage and Neurodegeneration

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Mitochondrial Dynamics and Neurodegeneration

Abstract

Under neurodegenerative conditions, abnormal mitochondrial morphology is often associated with synaptic injury and neuronal damage. Mitochondrial fission and fusion are dynamic processes that represent a key feature controlling mitochondrial structure and morphology. Members of the dynamin superfamily of GTPases and associated proteins are known to function in both mitochondrial fission and fusion. For example, mitofusin and OPA1 are essential for mitochondrial fusion, and dynamin-related protein 1 (Drp1), along with critical partners, mediates mitochondrial fission. In this review, we primarily focus on the mitochondrial fission protein Drp1, and discuss recent insights that may potentially link aberrant S-nitrosylation Drp1 as well as other posttranslational modifications (phosphorylation, sumoylation, and ubiquitination) to synaptic damage, neuronal cell injury, and cell death. We propose the hypothesis that dysfunctional Drp1 activity can contribute to the pathogenesis of neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases.

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Abbreviations

Aβ:

β-amyloid protein

ABAD:

Ab-binding alcohol dehydrogenase

AD:

Alzheimer’s disease

ADDL:

Ab-driven diffusible ligand

ADOA:

autosomal dominant optic atrophy

APP:

amyloid precursor protein

CDK5:

cyclin-dependent kinase 5

CMT2A:

Charcot-Marie-Tooth neuropathy type2A

Drp1:

dynamin-related protein 1

GED:

GTPase effector domain

HR:

heptad repeat

IMM:

inner mitochondrial membrane

MAPL:

mitochondrial-anchored protein ligase

Mfn:

mitofusin

MLS:

mitochondrial localization sequence

MOMP:

mitochondrial outer membrane permeabilization

NO:

nitric oxide

OMM:

outer mitochondrial membrane

Opa1:

optic atrophy protein 1

PD:

Parkinson’s disease

PTM:

posttranslational modification

SENP:

Sentrin/SUMO-specific protease

SUMO:

small ubiquitin-related modifier 1.

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Acknowledgments

This study was supported in part by NIH grants P01 HD29587, P01 ES01673, P30 NS057096, R01 EY05477, and R01 EY09024 (to S.A.L.). Additional support was provided by a grant from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A090013 and A092042) (to D.-H.C.).

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  1. Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Tomohiro Nakamura & Stuart A. Lipton

  2. Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Gyeonggi, 446–701, Korea

    Dong-Hyung Cho

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  1. Tomohiro Nakamura
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  2. Dong-Hyung Cho
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Correspondence to Stuart A. Lipton .

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  1. , Department of Pathology, Stanford University School of Medicine, Allardice Way 825, Stanford, 94305, California, USA

    Bingwei Lu

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Nakamura, T., Cho, DH., Lipton, S.A. (2011). Role of the Mitochondrial Fission Protein Drp1 in Synaptic Damage and Neurodegeneration. In: Lu, B. (eds) Mitochondrial Dynamics and Neurodegeneration. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1291-1_8

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