Review
Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases

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Abstract

The purpose of this article is to review the recent developments of abnormal mitochondrial dynamics, mitochondrial fragmentation, and neuronal damage in neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The GTPase family of proteins, including fission proteins, dynamin related protein 1 (Drp1), mitochondrial fission 1 (Fis1), and fusion proteins (Mfn1, Mfn2 and Opa1) are essential to maintain mitochondrial fission and fusion balance, and to provide necessary adenosine triphosphate to neurons. Among these, Drp1 is involved in several important aspects of mitochondria, including shape, size, distribution, remodeling, and maintenance of mitochondria in mammalian cells. In addition, recent advancements in molecular, cellular, electron microscopy, and confocal imaging studies revealed that Drp1 is associated with several cellular functions, including mitochondrial and peroxisomal fragmentation, phosphorylation, SUMOylation, ubiquitination, and cell death. In the last two decades, tremendous progress has been made in researching mitochondrial dynamics, in yeast, worms, and mammalian cells; and this research has provided evidence linking Drp1 to neurodegenerative diseases. Researchers in the neurodegenerative disease field are beginning to recognize the possible involvement of Drp1 in causing mitochondrial fragmentation and abnormal mitochondrial dynamics in neurodegenerative diseases. This article summarizes research findings relating Drp1 to mitochondrial fission and fusion, in yeast, worms, and mammals. Based on findings from the Reddy laboratory and others', we propose that mutant proteins of neurodegenerative diseases, including AD, PD, HD, and ALS, interact with Drp1, activate mitochondrial fission machinery, fragment mitochondria excessively, and impair mitochondrial transport and mitochondrial dynamics, ultimately causing mitochondrial dysfunction and neuronal damage.

Introduction

Increasing evidence suggests that structural and functional abnormalities in mitochondria are involved in aging and age-related neurodegenerative diseases, such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS) (Beal, 2005, Reddy and Beal, 2005, Lin and Beal, 2006, Reddy, 2006a, Reddy, 2006b, Reddy, 2007, Reddy, 2008; Reddy and Beal, 2008, Reddy and Reddy, in press). These structural abnormalities are caused by an imbalance in highly conserved, GTPase genes that are essential for mitochondrial division and mitochondrial fusion. Table 1 summarizes molecular features and biological functions involved in mitochondrial fission and fusion genes. GTPase genes–dynamin-related protein 1 (Drp1), fission 1 (Fis1), mitofusins 1 and 2 (Mfn1, Mfn2), and optic atrophy 1 (Opa1)–regulate, maintain, and remodel mammalian mitochondria (Chen and Chan, 2009).

Normal mammalian cells, including neurons, fission and fusion, via GTPase genes (Drp1, Fis1, Mfn1, Mfn2, and Opa1), balance equally and maintain mitochondrial dynamics and distribution (Chan, 2006, Chen and Chan, 2009). However, in aged neurons, in neurons exposed to toxins, and/or in neurons that express mutant proteins, an imbalance between fission and fusion leads to abnormalities in mitochondrial structure and function inhibits adenosine triphosphate (ATP) production, and damages neurons (Lin and Beal, 2006, Reddy, 2008). Recent research has revealed abnormal functions of fission and fusion genes and their involvement in neurodegenerative diseases (Reddy, 2008). The purpose of this article is to provide an overview of mitochondrial GTPase genes, with a particular focus on Drp1.

Section snippets

Mitochondrial genes

Structurally, mitochondrion is comprised of 2 lipid membranes: the matrix that harbors beta-oxidation and tricarboxylic acid, and the highly porous outer membrane and the inner membrane that restricts ionic flow to the mitochondrial matrix. The electron transport chain is localized in the inner membrane and participates in the transport of electrons and in the production of essential ATP (energy) for the cell.

Mitochondria constantly divide and fuse, altering their size and shape while traveling

Drp1 structure

Drp1 is critical for mitochondrial division, size, and shape, and for the distribution of mitochondria throughout the neuron, from cell body to axons, dendrites, and nerve terminals.

Drp1 function

Recent basic research on Drp1 in yeast, worms, and mammalian cells revealed that Drp1 is involved in several functions, including: 1) mitochondrial division, 2) mitochondrial distribution, 3) peroxisomal fragmentation, 4) phosphorylation, 5) ubiquitination, and 6) SUMOylation.

Drp1 and neurodegenerative diseases

Abnormal mitochondrial dynamics has been studied in yeast, worms, and mammalian cells. The involvement of Drp1 in mitochondria, and its role in maintaining the shape, size, and distribution of mitochondria, have been determined to be crucial for normal cell functioning. However, the role of Drp1 in maintaining the shape, size, and distribution of mitochondria has been investigated in only a few studies in AD, PD, and HD.

Drp1 expression, mitochondrial fragmentation and impaired mitochondrial transport in neurodegenerative diseases

Based on findings from the Reddy laboratory (Reddy et al., 2004, Reddy, 2008, Manczak et al., 2004, Manczak et al., 2005, Manczak et al., 2006, Manczak et al., 2010; Shirendeb and Reddy unpublished observations), and others (Barsoum et al., 2006, Dagda et al., 2009; Lutz et al., 2009; Sandebring et al., 2009, Magrané et al., 2009), we propose that an age-dependent, increased production and subsequent accumulation of mutant proteins in mitochondria (such as Aβ in AD, mutant Htt in HD, mutant

Conclusions and future directions

The science of mitochondrial dynamics (or fission fusion balance) is relatively new and has been studied in AD and PD. Currently, several investigators are studying abnormal mitochondrial dynamics in HD and ALS, and also in aging. Increasing evidence suggests that balanced mitochondrial fission and fusion are critically important in the maintenance of mitochondrial size, shape, distribution, and normal neuronal function. Impairments in mitochondrial fission and fusion cause irregular

Acknowledgments

This research presented was supported by NIH grants AG028072, AG026051, and RR00163, Alzheimer Association grant IIRG-09-92429, and Medivation, Inc.

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