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Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK

2021; Elsevier BV; Volume: 81; Issue: 18 Linguagem: Inglês

10.1016/j.molcel.2021.08.025

1097-4164

Che-Chia Hsu, Xian Zhang, Guihua Wang, Weina Zhang, Zhen Cai, Bo‐Syong Pan, Haiwei Gu, Chuan Xu, Guoxiang Jin, Xiang Xu, Rajesh Manne, Yan Jin, Wei Yan, Jingwei Shao, Tingjin Chen, Emily Lin, Amit Ketkar, Robert L. Eoff, Zhigang Xu, Zhong‐Zhu Chen, Hong‐yu Li, Hui‐Kuan Lin,

Metabolism, Diabetes, and Cancer

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.