Abstract
BackgroundAutosomal dominant optic atrophy (ADOA), a form of progressive bilateral blindness due to loss of retinal ganglion cells and optic nerve deterioration, arises predominantly from mutations in the nuclear gene for the mitochondrial GTPase, OPA1. OPA1 localizes to mitochondrial cristae in the inner membrane where electron transport chain complexes are enriched. While OPA1 has been characterized for its role in mitochondrial cristae structure and organelle fusion, possible effects of OPA1 on mitochondrial function have not been determined.ResultsMitochondria from six ADOA patients bearing OPA1 mutations and ten ADOA patients with unidentified gene mutations were studied for respiratory capacity and electron transport complex function. Results suggest that the nuclear DNA mutations that give rise to ADOA in our patient population do not alter mitochondrial electron transport.ConclusionWe conclude that the pathophysiology of ADOA likely stems from the role of OPA1 in mitochondrial structure or fusion and not from OPA1 support of oxidative phosphorylation.
Highlights
Autosomal dominant optic atrophy (ADOA), a form of progressive bilateral blindness due to loss of retinal ganglion cells and optic nerve deterioration, arises predominantly from mutations in the nuclear gene for the mitochondrial GTPase, OPA1
For OPA1-positive patient mitochondria, only slight reductions in all complex I rates were found when comparing the average rates from both complex I-linked substrates with the controls. These data suggest that OPA1 has no direct role in OXPHOS, individual variation in OXPHOS exists within the OPA1-positive ADOA patient mitochondria
No significant effects on respiratory capacity or specific electron transport chain enzyme activity were observed in mitochondria from OPA1-positive or OPA1-negative ADOA patients suggesting that ADOArelated gene defects alter mitochondrial function primarily by disruption of inner mitochondrial membrane topography
Summary
Autosomal dominant optic atrophy (ADOA), a form of progressive bilateral blindness due to loss of retinal ganglion cells and optic nerve deterioration, arises predominantly from mutations in the nuclear gene for the mitochondrial GTPase, OPA1. Autosomal dominant optic atrophy (ADOA) is a progressive form of bilateral blindness that shares the end-stage clinical characteristics of retinal gangln cell (RGC) death and optic nerve atrophy with the mitochondrial disease, Leber's hereditary optic neuropathy (LHON) [1]. OPA1 encodes a 960 amino acid mitochondrial dynamin-related GTPase that resides in the inner membrane cristae and plays an essential role in cristae structure and mitochondrial fusion [8,9,10,11,12,13,14,15,16]. The relationship between these roles for OPA1 and the relationship of either function to cellular energy production remain to be elucidated
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