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 and Hongzhe Sun ()
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Haibo Wang: The University of Hong Kong
Ligang Hu: The University of Hong Kong
Hongyan Li: The University of Hong Kong
Yau-Tsz Lai: The University of Hong Kong
Xueying Wei: The University of Hong Kong
Xiaohan Xu: The University of Hong Kong
Zhenkun Cao: The University of Hong Kong
Huiming Cao: Jianghan University
Qianya Wan: City University of Hong Kong
Yuen-Yan Chang: The University of Hong Kong
Aimin Xu: The University of Hong Kong
Qunfang Zhou: Chinese Academy of Sciences
Guibin Jiang: Chinese Academy of Sciences
Ming-Liang He: City University of Hong Kong
Hongzhe Sun: The University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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).

Date: 2023
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DOI: 10.1038/s41467-023-37351-w

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