title: Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy.
abstract: The most frequent form of hereditary blindness, autosomal dominant optic atrophy (ADOA), is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca(2+) uptake (Fülöp et al., 2011). Therefore we studied mitochondrial Ca(2+) metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell-inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca(2+) signals. The present data indicate that enhanced mitochondrial Ca(2+) uptake is a pathogenetic factor in the progress of ADOA.
authors.affiliation: Department of Physiology, Semmelweis University Medical School, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Fülöp
authors.affiliation: Laboratory of Molecular Physiology, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Rajki
authors.affiliation: Department of Ophthalmology, Semmelweis University Medical School, Budapest, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Maka
authors.affiliation: Department of Genomic Medicine and Rare Diseases, Semmelweis University Medical School, Budapest, Hungary.
authors.forename: Mária Judit
authors.initials: MJ
authors.lastname: Molnár
authors.affiliation: Department of Physiology, Semmelweis University Medical School, Budapest, Hungary. Electronic address: spat@eok.sote.hu.
authors.forename: András
authors.initials: A
authors.lastname: Spät
mesh_terms: D000328:Adult; D017209:Apoptosis; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D007438:Introns; D008297:Male; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D029241:Optic Atrophy, Autosomal Dominant / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D001920:Bradykinin; D002118:Calcium
keywords: Apoptosis; Calcium ion; Fibroblast; Ganglion cell; Mitochondria; OPA1; Optic atrophy