Regulation of mitochondrial FoF1ATPase activity by Sirt3-catalyzed deacetylation and its deficiency in human cells harboring 4977bp deletion of mitochondrial DNA

Yu Ting Wu, Hsin Chen Lee, Chen Chung Liao, Yau Huei Wei*

*此作品的通信作者

研究成果: Article同行評審

72 引文 斯高帕斯(Scopus)

摘要

Sirt3, a mitochondrial NAD+-dependent deacetylase, is regarded as a potential regulator in cellular metabolism. However, the role of Sirt3 in the regulation of mitochondrial FoF1ATPase and the linkage to mitochondrial diseases is unclear. In this study, we demonstrated a role of Sirt3 in the regulation of FoF1ATPase activity in human cells. Knockdown of Sirt3 in 143B cells by shRNA transfection caused increased acetylation levels of the α and OSCP subunits of FoF1ATPase. We showed that Sirt3 physically interacted with the OSCP and led to its subsequent deacetylation. By incubation of mitochondria with the purified Sirt3 protein, Sirt3 could regulate FoF1ATPase activity through its deacetylase activity. Moreover, suppression of Sirt3 reduced the FoF1ATPase activity, consequently decreased the intracellular ATP level, diminished the capacity of mitochondrial respiration, and compromised metabolic adaptability of 143B cells to the use of galactose as the energy source. In human cells harboring ≅85% of mtDNA with 4977bp deletion, we showed that oxidative stress induced a reduction of Sirt3 expression, and an increased acetylation of the OSCP subunit of FoF1ATPase. Importantly, the expression of Sirt3 was also decreased in the skin fibroblasts from patients with CPEO syndrome. We further demonstrated that oxidative stress induced by 5-10μM of menadione impaired the Sirt3-mediated deacetylation and activation on FoF1ATPase activity through decreasing the protein level of Sirt3. Our findings suggest that increased intracellular ROS levels might modulate the expression of Sirt3 which deacetylates and activates FoF1ATPase in human cells with mitochondrial dysfunction caused by a pathogenic mtDNA mutation.

原文English
頁(從 - 到)216-227
頁數12
期刊Biochimica et Biophysica Acta - Molecular Basis of Disease
1832
發行號1
DOIs
出版狀態Published - 1月 2013

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