Critical dependence of neurons on mitochondrial dynamics

doi:10.1016/j.ceb.2006.06.004

Current Opinion in Cell Biology

Volume 18, Issue 4, August 2006, Pages 453-459

https://doi.org/10.1016/j.ceb.2006.06.004 Get rights and content

The selective disruption of certain cell types — notably neurons — in diseases involving mitochondrial dysfunction is thought to reflect the high-energy requirements of these cells, but few details are known. Recent studies have provided clues to the cellular basis of this mitochondrial requirement. Mitochondria are regionally organized within some nerve cells, with higher accumulations in the soma, the hillock, the nodes of Ranvier and the nerve terminal. In the synaptic region, mitochondria regulate calcium and ATP levels, thereby maintaining synaptic transmission and structure. Defects in mitochondrial dynamics can cause deficits in mitochondrial respiration, morphology and motility. Moreover, mutations in the mitochondrial fusion genes Mitofusin-2 and OPA1 lead to the peripheral neuropathy Charcot-Marie-Tooth type 2A and dominant optic atrophy. Perhaps it is the strict spatial and functional requirements for mitochondria in neurons that cause defects in mitochondrial fusion to manifest primarily as neurodegenerative diseases.

Introduction

Mitochondria are critical for many cellular functions — including oxidative phosphorylation, intermediary metabolism, calcium buffering and apoptosis regulation — that are important to all cells. Yet mitochondrial diseases generally affect only a subset of tissues, most notably muscle and neurons. Why are these cells more prone to mitochondrial insult? In this review, we describe recent studies that have furthered our understanding of why neurons are particularly dependent on mitochondria. In particular, we explore how defects in mitochondrial dynamics can lead to neuronal disease.

Section snippets

Mitochondria and neurons

The prevalence of neuronal diseases associated with mutations in mitochondrial genes indicates an important functional relationship between mitochondria and neurons (Table 1). Classic mitochondrial encephalomyopathies caused by mtDNA mutations are often characterized by neurological symptoms [1, 2•]. Prominent are those associated with movement, such as ataxia, dysarthria and peripheral neuropathy. Mutations in mitochondrial proteins that are encoded in the nucleus have also been linked to

Dynamics of mitochondria

In a typical mammalian cell, the mitochondria are highly dynamic and undergo continual fusion and fission [10^•]. These processes control not only the overall morphology of the mitochondrial population, but also its proper function. Three proteins have been shown to be central to the fusion of mammalian mitochondria (Figure 1a). The mitofusins, Mfn1 and Mfn2, are essential GTPases localized to the mitochondrial outer membrane [11, 12, 13]. Deletion of either Mfn1 or Mfn2 results in mitochondrial

Mitochondrial dynamics and Charcot-Marie-Tooth disease

The predominant gene affected in Charcot-Marie-Tooth (CMT) disease type 2A is Mfn2 [26, 27, 28•]. CMT refers to a group of hereditary peripheral neuropathies that affect both motor and sensory nerves [29, 30]. All patients demonstrate motor defects in at least the lower extremities, but other clinical aspects vary greatly. Over time, the primary neuronal defects can lead to muscle atrophy. Genetically, CMT is heterogeneous with at least 24 different genes associated with the disease, and both

Mitochondrial dynamics and dominant optic atrophy

Dominant optic atrophy (DOA), the most commonly inherited optic neuropathy, generally presents in childhood as bilateral loss of visual acuity associated with the clinical finding of optic nerve pallor, an indication of degeneration [35]. This disease is caused by loss of retinal ganglion cells (RGCs), which line the front of the retina and give rise to the fibers of the optic nerve. Three loci (OPA1, OPA4, OPA5) have been linked with DOA [36, 37, 38, 39]. OPA1 is by far the most common cause

Possible mechanisms of neuronal dysfunction

With both CMT2A and DOA, little information is available on the histopathology of mitochondria in disease tissues. In addition, it is unclear what kind of mitochondrial dysfunction is caused by the Mfn2 and OPA1 disease alleles. However, on the basis of information about the cellular functions of these proteins, several possibilities can be proposed (Figure 2). First, the mutations in Mfn2 and OPA1 may impair respiratory capacity, by analogy with cells lacking Mfn or OPA1 function [15^••].

Conclusions

Clearly, mitochondrial function is critical for neuronal function, as demonstrated by the many neuronal symptoms associated with mtDNA mutations. Localization of mitochondria at particular segments of neuronal cells is also critical for neuronal function. This localization requires proper transport and morphology of mitochondria. Because mitochondrial dynamics influences both mitochondrial function and motility, the involvement of two mitochondrial fusion proteins, Mfn2 and OPA1, in

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

Work in D. Chan's laboratory is funded by the NIH (GM062967), the Muscular Dystrophy Association, and the United Mitochondrial Disease Foundation. D. Chan is a Bren Scholar.

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Citation Excerpt :
If the mitochondria receive cell death-inducing signals, the membrane permeability is altered, culminating in the depletion of ATP synthesis and in the liberation of cell death-activating proteins in the cytoplasm (Loeffler and Kroemer, 2000; Grivicich et al., 2007). Due to the large amount of energy required by synapses, it is indispensable that mitochondria function normally (Chen and Chan, 2006). For this reason, the dilatation of the mitochondria reported in the present study may result in functional impairment of the neurons.
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Critical dependence of neurons on mitochondrial dynamics

Introduction

Section snippets

Mitochondria and neurons

Dynamics of mitochondria

Mitochondrial dynamics and Charcot-Marie-Tooth disease

Mitochondrial dynamics and dominant optic atrophy

Possible mechanisms of neuronal dysfunction

Conclusions

References and recommended reading

Acknowledgements

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