Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity

Jia Li, Caroline Romestaing, Xianlin Han, Yuan Li, Xinbao Hao, Yinyuan Wu, Chao Sun, Xiaolei Liu, Leonard S. Jefferson, Jingwei Xiong, Kathryn F. Lanoue, Zhijie Chang, Christopher J. Lynch, Huayan Wang, Yuguang Shi

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

Oxidative stress causes mitochondrial dysfunction and metabolic complications through unknown mechanisms. Cardiolipin (CL) is a key mitochondrial phospholipid required for oxidative phosphorylation. Oxidative damage to CL from pathological remodeling is implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, and other metabolic diseases. Here, we show that ALCAT1, a lyso-CL acyltransferase upregulated by oxidative stress and diet-induced obesity (DIO), catalyzes the synthesis of CL species that are highly sensitive to oxidative damage, leading to mitochondrial dysfunction, ROS production, and insulin resistance. These metabolic disorders were reminiscent of those observed in type 2 diabetes and were reversed by rosiglitazone treatment. Consequently, ALCAT1 deficiency prevented the onset of DIO and significantly improved mitochondrial complex I activity, lipid oxidation, and insulin signaling in ALCAT1-/- mice. Collectively, these findings identify a key role of ALCAT1 in regulating CL remodeling, mitochondrial dysfunction, and susceptibility to DIO.

Original languageEnglish (US)
Pages (from-to)154-165
Number of pages12
JournalCell Metabolism
Volume12
Issue number2
DOIs
StatePublished - Aug 4 2010

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ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Li, J., Romestaing, C., Han, X., Li, Y., Hao, X., Wu, Y., Sun, C., Liu, X., Jefferson, L. S., Xiong, J., Lanoue, K. F., Chang, Z., Lynch, C. J., Wang, H., & Shi, Y. (2010). Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity. Cell Metabolism, 12(2), 154-165. https://doi.org/10.1016/j.cmet.2010.07.003