A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency

In recent years, genetic defects of the mitochondrial genome (mtDNA) were s hown to be associated with a heterogeneous group of disorders, known as mit ochondrial diseases(1,2), but the cellular events deriving from the molecul ar lesions and the mechanistic basis of the specificity of the syndromes ar e still incompletely understood. Mitochondrial calcium (Ca2+) homeostasis d epends on close contacts with the endoplasmic reticulum(3) and is essential in modulating organelle function(4-6). Given the strong dependence of mito chondrial Ca2+ uptake on the membrane potential and the intracellular distr ibution of the organelle, both of which may be altered in mitochondrial dis eases, we investigated the occurrence of defects in mitochondrial Ca2+ hand ling in living cells with either the tRNA(Lys) mutation of MERRF (myoclonic epilepsy with ragged-red fibers)(7-9) or the ATPase mutation of NARP (neur ogenic muscle weakness, ataxia and retinitis pigmentosa)(10-13). There was a derangement of mitochondrial Ca2+ homeostasis in MERRF, but not in NARP c ells, whereas cytosolic Ca2+ responses were normal in both cell types. Trea tment of MERRF cells with drugs affecting organellar Ca2+ transport mostly restored both the agonist-dependent mitochondrial Ca2+ uptake and the ensui ng stimulation of ATP production. These results emphasize the differences i n the cellular pathogenesis of the various mtDNA defects and indicate speci fic pharmacological approaches to the treatment of some mitochondrial disea ses.