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 (Δψmit) 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.
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Abbreviations
- Ca2+:
-
calcium
- Cyt:
-
cytosol
- [Ca2+]cyt:
-
cytosolic-free Ca2+ concentration
- ER:
-
endoplasmic reticulum
- [Ca2+]er:
-
endoplasmic reticulum Ca2+ concentration
- [Ca2+]mit:
-
mitochondrial-free Ca2+ concentration
- IP3, inositol 1, 4:
-
5-triphosphate
- Δψm:
-
mitochondrial potential
- [ATP]mit:
-
mitochondria ATP-free concentration
- OXPHOS:
-
oxidative phosphorylation
- PMCA:
-
plasma-membrane Ca2+ ATPase
- ROS:
-
reactive oxygen species
- SERCA2:
-
sarco-endoplasmic reticulum Ca2+ ATPase 2
- SDHA:
-
succinate dehydrogenase A subunit
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Acknowledgements
High-resolution imaging analyses were performed in Pasteur institute (PFID), Paris, France. Fluorescence imagery analyses were performed in the imaging core facility of Necker-Enfants Malades, Paris V University, France. We thank the vector core of the university Hospital of Nantes supported by the association Française contre les myopathies (AFM) for producing the Adenovirus vectors. This work was supported by grants from INSERM (Institut National de Santé et Recherche Médicale), AFM (11456 and 13291) and la Fondation pour la Recherche Médicale (FRM) (DEQ20071210550). C Caspersen was supported by ‘region Ile de France’ postdoctoral fellowship. M Chami was supported by an INSERM young researcher contract and by the Italian Institute of Technology funds. E Mbaya was supported by a doctoral fellowship from Congo Ministry. We gratefully acknowledge the Ecole de l’INSERM for supporting the MD-PhD curriculum of B Oulès, GAR was supported by grants from the Welcome trust (081958/Z/07/Z), MRC (90401641), NIH (DK071962-01) and EU (FP6 ‘SAVEBETA’). MP is supported by Muscular Dystrophy Association and Kennedy Disease Association Grants.
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Mbaya, E., Oulès, B., Caspersen, C. et al. Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency. Cell Death Differ 17, 1855–1866 (2010). https://doi.org/10.1038/cdd.2010.51
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DOI: https://doi.org/10.1038/cdd.2010.51
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