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

Mounia Chami (1) , Eleonore Mbaya-Moutula (1) , Bénédicte Oulès (1) , Casper Caspersen (1) , Rachida Tacine (1) , Hélène Massinet (1) , Dominique Chrétien (1) , Arnold Munnich (1) , Agnes Rotig (1) , Rosario Rizzuto (1) , Guy A. Rutter (1) , Patrizia Paterlini-Bréchot (1) , Maria Pennuto (1)

1 neuroscience and barin technology

Despite advanced knowledge on the genetic basis of oxidative phosphorylation (OXPHOS)-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 prior to 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 (∆ψmit) loss, [ATP] reduction and increased Reactive Oxygen Species (ROS) production. cytosolic and mitochondrial Ca2+ overload are linked to increased 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 role for Ca2+ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency.

Mots clés: calcium; mitochondria; bioenergetics; cell death; respiratory chain

Mounia Chami, Eleonore Mbaya-Moutula, Bénédicte Oulès, Casper Caspersen, Rachida Tacine, et al.. Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.51⟩. ⟨hal-00538097⟩