Mitochondrial oxidative phosphorylation in autosomal dominant optic atrophy

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.

Heart Failure and Mitochondrial Dysfunction

“…43 In contrast, other OPA1 mutations did not affect mitochondrial activity and bioenergetics. 47 These results indicate that there are key OPA1 domains for mitochondrial function. Greater understanding of post-translational modifications and identification of proteins that interact with OPA1 will provide further insight into the mechanism(s) by which some ADOA OPA1 mutations can cause disease, and yet not effect measured mitochondrial function.…”

Mitochondrial Dynamics and Heart Failure

“…Furthermore, after exercise the recovery time of PCr levels was markedly prolonged (28 vs. 19 sec, p<0.01). Some OPA1 mutations did not alter mitochondrial activity or bioenergetics (122). Thus, there are select OPA1 domains required to maintain normal mitochondrial function.…”

Mitochondrial Dynamics in Heart Failure

“…Studies of fibroblasts from patients with specific OPA1 mutations (c.2708delTTAG, c.1705 + 1G4T, c.1516 + 1G4, c.2819-2A4C, c.1346_1347insC) show impaired ATP synthesis driven by complex I substrates and decreased rates of mitochondrial fusion (26). In contrast other OPA1 mutations (c1410_144314del38, c.239A>G, c.2883A>C, c.2522A>G, c.2780T>A, c.1654delT, c.1929delC, c.2708delTTAG) did not affect mitochondrial activity and bioenergetics (30). These results suggest that there are key domains in OPA1 for mitochondrial function, and that further knowledge of post-translational modifications, protein folding and proteins that interact with OPA1 should shed light on the mechanism by which the ADOA OPA1 mutations cause disease without effecting measured mitochondrial function.…”