Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

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Abstract

Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca2+ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Δmit) loss, ATP reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca2+ overload are linked to increased endoplasmic reticulum (ER) Ca2+ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased Ca2+mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular Ca2+ activated on the one hand a compensatory Ca2+-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca2+ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency. © 2010 Macmillan Publishers Limited All rights reserved.

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Mbaya, E., Oulès, B., Caspersen, C., Tacine, R., Massinet, H., Pennuto, M., … Chami, M. (2010). Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency. Cell Death and Differentiation, 17(12), 1855–1866. https://doi.org/10.1038/cdd.2010.51

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