A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function

Abstract

Autosomal dominant optic atrophy (ADOA), the commonest cause of inherited optic atrophy, is caused by mutations in the ubiquitously expressed gene optic atrophy 1 (OPA1), involved in fusion and biogenesis of the inner membrane of mitochondria. Bioenergetic failure, mitochondrial network abnormalities and increased apoptosis have all been proposed as possible causal factors. However, their relative contribution to pathogenesis as well as the prominent susceptibility of the retinal ganglion cell (RGC) in this disease remains uncertain. Here we identify a novel deletion of OPA1 gene in the GTPase domain in three patients affected by ADOA. Muscle biopsy of the patients showed neurogenic atrophy and abnormal morphology and distribution of mitochondria. Confocal microscopy revealed increased mitochondrial fragmentation in fibroblasts as well as in myotubes, where mitochondria were also unevenly distributed, with clustered organelles alternating with areas where mitochondria were sparse. These abnormalities were not associated with altered bioenergetics or increased susceptibility to pro-apoptotic stimuli. Therefore, changes in mitochondrial shape and distribution can be independent of other reported effects of OPA1 mutations, and therefore may be the primary cause of the disease. The arrangement of mitochondria in RGCs, which degenerate in ADOA, may be exquisitely sensitive to disturbance, and this may lead to bioenergetic crisis and/or induction of apoptosis. Our results highlight the importance of mitochondrial dynamics in the disease per se, and point to the loss of the fine positioning of mitochondria in the axons of RGCs as a possible explanation for their predominant degeneration in ADOA.

High-Dialysate-Glucose-Induced Oxidative Stress and Mitochondrial-Mediated Apoptosis in Human Peritoneal Mesothelial Cells

“…Mitochondria are dynamic organelles, undergoing constant fission and fusion regulated by machinery involving large GTPase family proteins and their regulators [22]. Perturbation of the dynamic balance between mitochondrial fusion and fission results in mitochondrial fragmentation, leading to impairment of oxidative phosphorylation [23]. Mitochondrial fragmentation has been demonstrated to be a common feature in stress-induced apoptosis.…”

PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling

“…Quantitative evaluation of mitochondria elongation was performed by deriving a numerical parameter based on the method in (Spinazzi et al, 2008). Cells were imaged after incubation with Mitotracker red or green at a concentration of 50 nM for 3 min at 37°C.…”

Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics

“…Overexpression of a truncated form of MFN2 (⌬602-757) enhances mitochondrial metabolism independent of fusion activity (51); however, other MFN2 mutants did not induce metabolic alterations (68). Some OPA1 mutants showed impaired ATP synthesis driven by complex I substrates and decreased rates of mitofusion (77); however, other mutants showed normal mitochondrial activity and bioenergetics (65). One study (16) reported that overexpression of OPA1 did not modify mitochondrial metabolism in MEF cells.…”