(mentions CMT 2A) Retinal ganglion cells neurodegeneration in mitochondrial

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Biochim Biophys Acta. 2009 Mar 4.

Retinal ganglion cells neurodegeneration in mitochondrial inherited disorders.

Carelli V, Morgia CL, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA.

Department of Neurological Sciences, University of Bologna, Italy.

Since the early days of mitochondrial medicine, it has been clear that optic

atrophy is a very common and sometimes singular pathological feature in

mitochondrial disorders. The first point mutation of mitochondrial DNA (mtDNA)

associated with the maternally inherited blinding disorder, Leber's hereditary

optic neuropathy (LHON), was recognized in 1988.

In 2000, the other blinding disorder, dominant optic atrophy (DOA) Kjer type,

was found associated with mutations in the nuclear gene OPA1 that encodes a

mitochondrial protein. Besides these two non-syndromic optic neuropathies, optic

atrophy is a prominent feature in many other neurodegenerative diseases that are

now recognized as due to primary mitochondrial dysfunction.

We will consider mtDNA based syndromes such as LHON/dystonia/Mitochondrial

Encephalomyopahty Lactic Acidosis Stroke-like (MELAS)/Leigh overlapping

syndrome, or nuclear based diseases such as Friedreich Ataxia (mutations in FXN

gene), deafness-dystonia-optic atrophy (Mohr-Tranebjerg) syndrome (mutations in

TIMM8A), complicated hereditary spastic paraplegia (mutations in SPG7), DOA

" plus " syndromes (mutations in OPA1), Charcot-Marie-Tooth type 2A (CMT2A) with

optic atrophy or hereditary motor and sensory neuropathy type VI (HMSN VI)

(mutations in MFN2), and Costeff syndrome and DOA with cataract (mutations in

OPA3).

Thus, genetic errors in both nuclear and mitochondrial genomes often lead to

retinal ganglion cell death, a specific target for mitochondrial mediated

neurodegeneration. Many mechanisms have been studied and proposed as the bases

for the pathogenesis of mitochondrial optic neuropathies including bioenergetic

failure, oxidative stress, glutamate toxicity, abnormal mitochondrial dynamics

and axonal transport, and susceptibility to apoptosis.