期刊
CELL DEATH AND DIFFERENTIATION
卷 17, 期 12, 页码 1855-1866出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2010.51
关键词
mitochondria; respiratory chain pathologies; calcium; bioenergetics; SERCA; PMCA
资金
- INSERM (Institut National de Sante et Recherche Medicale)
- AFM [11456, 13291]
- La Fondation pour la Recherche Medicale (FRM) [DEQ20071210550]
- Region Ile de France
- Italian Institute of Technology
- Congo Ministry
- Ecole de l'INSERM
- Welcome trust [081958/Z/07/Z]
- MRC [90401641]
- NIH [DK071962-01]
- EU
- Muscular Dystrophy Association
- Kennedy Disease Association
- Medical Research Council [G0401641] Funding Source: researchfish
- MRC [G0401641] Funding Source: UKRI
- Wellcome Trust [081958/Z/07/Z] Funding Source: Wellcome Trust
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 Ca(2+) signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Delta psi(mit)) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca(2+) overload are linked to increased endoplasmic reticulum (ER) Ca(2+) leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca(2+)](mlt) is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca(2+)] activated on the one hand a compensatory Ca(2+)-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca(2+) signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency. Cell Death and Differentiation (2010) 17, 1855-1866; doi:10.1038/cdd.2010.51; published online 21 May 2010
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