Abstract
Mitochondrial Ca2+ uptake controls cellular functions as diverse as aerobic metabolism, cytosolic Ca2+ signalling and mitochondrial participation in apoptosis. Modulatory inputs converging on the organelle can regulate this process, determining the final outcome of Ca2+-mediated cell stimulation. We investigated in HeLa cells and primary skeletal myotubes the effect on Ca2+ signalling of the transcriptional peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α), which triggers organelle biogenesis and modifies the mitochondrial proteome. PGC-1α selectively reduced mitochondrial Ca2+ responses to cell stimulation by reducing the efficacy of mitochondrial Ca2+ uptake sites and increasing organelle volume. In turn, this affected ER Ca2+ release and cytosolic responses in HeLa cells. Most importantly, the modulation of mitochondrial Ca2+ uptake significantly reduced cellular sensitivity to the Ca2+-mediated proapoptotic effect of C2 ceramide. These results reveal a primary role of PGC-1α in shaping mitochondrial participation in calcium signalling, that underlies its protective role against stress and proapoptotic stimuli in pathophysiological conditions.
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Abbreviations
- ACh:
-
acetylcholine
- CCh:
-
carbamylcholine
- [Ca2+]c:
-
cytosolic [Ca2+]
- [Ca2+]er:
-
endoplasmic reticulum [Ca2+]
- [Ca2+]m:
-
mitochondrial [Ca2+]
- [Ca2+]sr:
-
sarcoplasmic reticulum [Ca2+]
- cytAEQ:
-
cytosolic aequorin
- ER:
-
endoplasmic reticulum
- erAEQmut:
-
endoplasmic reticulum-targeted mutated aequorin
- FCCP:
-
carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone
- IP3:
-
inositol 1,4,5 trisphosphate
- IP3R:
-
inositol 1,4,5 trisphosphate receptor
- mAchR:
-
muscarinic Ach receptor
- mtAEQmut:
-
mitochondrially targeted mutated aequorin
- mtGFP:
-
mitochondrially targeted green fluorescent protein
- MCU:
-
mitochondrial Ca2+ uniporter
- PPAR-γ:
-
peroxisome-proliferator-activated-receptor-γ
- PGC-1α:
-
peroxisome-proliferator-activated-receptor-γ-coactivator-1α
- SERCA:
-
sarco/endoplasmic reticulum Ca2+-ATPase
- SR:
-
sarcoplasmic reticulum
- srAEQmut:
-
sarcoplasmic reticulum-targeted mutated aequorin
- TMRM:
-
tetramethyl-rhodamine-methyl-esther
- UCP:
-
uncoupling protein
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Acknowledgements
We thank Drs. M Duchen, KE Fogarty and E Rapizzi for their valuable help in image and analysis and discussion, and Dr. KD Becker (MitoKor) for providing the human PGC-1α/pcDNA/TO cDNA. This work was supported by grants from Telethon-Italy (Grants no. 1285 and GTF02013), the Italian Association for Cancer Research (AIRC), the Human Frontier Science Program, the Italian University Ministry (MURST and FIRB), the Italian Space Agency (ASI). GV was a recipient of an EMBO long-term fellowship. Part of the work by GS was supported by a Marie-Curie individual fellowship (HPMF-CT-2000-00644).
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Bianchi, K., Vandecasteele, G., Carli, C. et al. Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α. Cell Death Differ 13, 586–596 (2006). https://doi.org/10.1038/sj.cdd.4401784
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DOI: https://doi.org/10.1038/sj.cdd.4401784
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