CMT 2A: Dysregulation of mitochondrial fusion and fission: an emerging concept i

[Guest guest]

Acta Neuropathol (Berl). 2006 Feb 9;:1-8

Dysregulation of mitochondrial fusion and fission: an emerging

concept in neurodegeneration.

S.

Department of Neuropathology, Bonn University Medical Center, Sigmund-

Freud-Str. 25, 53105, Bonn, Germany, stephan.frank@....

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.