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

Abstract

In recent years, genetic defects of the mitochondrial genome (mtDNA) were shown to be associated with a heterogeneous group of disorders, known as mitochondrial diseases^1,2, but the cellular events deriving from the molecular lesions and the mechanistic basis of the specificity of the syndromes are still incompletely understood. Mitochondrial calcium (Ca²⁺) homeostasis depends on close contacts with the endoplasmic reticulum³ and is essential in modulating organelle function^4,5,6. Given the strong dependence of mitochondrial Ca²⁺ uptake on the membrane potential and the intracellular distribution of the organelle, both of which may be altered in mitochondrial diseases, we investigated the occurrence of defects in mitochondrial Ca²⁺ handling in living cells with either the tRNA^Lys mutation of MERRF (myoclonic epilepsy with ragged-red fibers)^7,8,9 or the ATPase mutation of NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa)^{10,11,G mutation in the ATPase 6 (subunit a) gene at position 8993 of mtDNA. Biochim. Biophys. Acta 1271, 349–357 (1995)." href="/articles/nm0899_951#ref12" aria-label="Reference 12" data-track="click" data-track-action="reference anchor" data-track-label="link">12,13}. There was a derangement of mitochondrial Ca²⁺ homeostasis in MERRF, but not in NARP cells, whereas cytosolic Ca²⁺ responses were normal in both cell types. Treatment of MERRF cells with drugs affecting organellar Ca²⁺ transport mostly restored both the agonist-dependent mitochondrial Ca²⁺ uptake and the ensuing stimulation of ATP production. These results emphasize the differences in the cellular pathogenesis of the various mtDNA defects and indicate specific pharmacological approaches to the treatment of some mitochondrial diseases.