期刊
FASEB JOURNAL
卷 33, 期 12, 页码 13176-13188出版社
WILEY
DOI: 10.1096/fj.201901136R
关键词
mitochondria; calcium; ER stress; metabolism; bioenergetics
资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) CEPID Grants [2014-10492-0, 2013/07937-8]
- CAPES (Coordenacao de Aperfeicoamento de Pessoal de N'ivel Superior) [001]
- Conselho Nacional de Pesquisa e Desenvolvimento (CNPq)
- U.S. National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK099618-02, RO1DK56690]
- University of California, Los Angeles (UCLA) Department of Medicine Chair commitment
- University of California, San Diego (UCSD)/UCLA Diabetes Research Center pilot grant
- NIH/NIDDK [P30 DK063491]
- Sao Paulo Research Foundation (FAPESP) [2014/24511-7]
- CAPES
- FAPESP [2017/14713-0, 2016/18633-8]
Changes in mitochondrial size and shape have been implicated in several physiologic processes, but their role in mitochondrial Ca2+ uptake regulation and overall cellular Ca2+ homeostasis is largely unknown. Here we show that modulating mitochondrial dynamics toward increased fusion through expression of a dominant negative (DN) form of the fission protein [dynamin-related protein 1 (DRP1)1 markedly increased both mitochondrial Ca2+ retention capacity and Ca2+ uptake rates in permeabilized C2C12 cells. Similar results were seen using the pharmacological fusion-promoting M1 molecule. Conversely, promoting a fission phenotype through the knockdown of the fusion protein mitofusin (MFN)-2 strongly reduced the mitochondrial Ca2+ (u)ptake speed and capacity in these cells. These changes were not dependent on modifications in mitochondrial calcium uniporter expression, inner membrane potentials, or the mitochondrial permeability transition. Implications of mitochondrial morphology modulation on cellular calcium homeostasis were measured in intact cells; mitochondrial fission promoted lower basal cellular calcium levels and lower endoplasmic reticulum (ER) calcium stores, as indicated by depletion with thapsigargin. Indeed, mitochondrial fission was associated with ER stress. Additionally, the calcium-replenishing process of store-operated calcium entry was impaired in MFN2 knockdown cells, whereas DRP1-DN promoted fusion resulted in faster cytosolic Ca2+ increase rates. Overall, our results show a novel role for mitochondrial morphology in the regulation of mitochondrial Ca2+ uptake, which impacts cellular Ca2+ homeostasis.
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