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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 diseases1,2, 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 function4,5,6. 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 tRNALys 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)10,11,12,13. 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.

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Figure 1: Histamine-dependent changes in mitochondrial and cytosolic calcium concentrations in MERRF, NARP and control cybrids.
Figure 2: Effect of CGP37157, a specific inhibitor of mitochondrial Ca2+ efflux, on the histamine-dependent mitochondrial and cytosolic calcium concentrations in control, MERRF and NARP cells.
Figure 3: Agonist-dependent stimulation of mitochondrial ATP production in control, MERRF and NARP cells.

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Acknowledgements

We thank T. Pozzan and P. Magalhães for criticism and discussion, and G. Ronconi, M. Santato, B. Filiano and E. Davidson for technical assistance. The work was supported by funds from 'Telethon' (project number 850) and from the Italian University and Health Ministries to R.R., and grants from the National Institutes of Health (NS28828, NS11766 and HD32062) and the Muscular Dystrophy Association of USA to E.A.S. and M.P.K.

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Correspondence to Rosario Rizzuto.

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Brini, M., Pinton, P., King, M. et al. A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency. Nat Med 5, 951–954 (1999). https://doi.org/10.1038/11396

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