Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress
Haibo Wang, Ligang Hu, Hongyan Li, Yau‐Tsz Lai, Xueying Wei, Xiaohan Xu, Zhenkun Cao, Huiming Cao, Qianya Wan, Yuen‐Yan Chang, Aimin Xu, Qunfang Zhou, Guibin Jiang, Ming‐Liang He, Hongzhe Sun
Abstract
Chromium(III) is extensively used as a supplement for muscle development and the treatment of diabetes mellitus. However, its mode of action, essentiality, and physiological/pharmacological effects have been a subject of scientific debate for over half a century owing to the failure in identifying the molecular targets of Cr(III). Herein, by integrating fluorescence imaging with a proteomic approach, we visualized the Cr(III) proteome being mainly localized in the mitochondria, and subsequently identified and validated eight Cr(III)-binding proteins, which are predominately associated with ATP synthesis. We show that Cr(III) binds to ATP synthase at its beta subunit via the catalytic residues of Thr213/Glu242 and the nucleotide in the active site. Such a binding suppresses ATP synthase activity, leading to the activation of AMPK, improving glucose metabolism, and rescuing mitochondria from hyperglycaemia-induced fragmentation. The mode of action of Cr(III) in cells also holds true in type II diabetic male mice. Through this study, we resolve the long-standing question of how Cr(III) ameliorates hyperglycaemia stress at the molecular level, opening a new horizon for further exploration of the pharmacological effects of Cr(III).