Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.
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.
['Hsu|Che-Chia|CC|', 'Zhang|Xian|X|', 'Wang|Guihua|G|', 'Zhang|Weina|W|', 'Cai|Zhen|Z|', 'Pan|Bo-Syong|BS|', 'Gu|Haiwei|H|', 'Xu|Chuan|C|', 'Jin|Guoxiang|G|', 'Xu|Xiangshang|X|', 'Manne|Rajesh Kumar|RK|', 'Jin|Yan|Y|', 'Yan|Wei|W|', 'Shao|Jingwei|J|', 'Chen|Tingjin|T|', 'Lin|Emily|E|', 'Ketkar|Amit|A|', 'Eoff|Robert|R|', 'Xu|Zhi-Gang|ZG|', 'Chen|Zhong-Zhu|ZZ|', 'Li|Hong-Yu|HY|', 'Lin|Hui-Kuan|HK|']
D055372:AMP-Activated Protein Kinases D000818:Animals D002460:Cell Line D006801:Humans D007294:Inositol D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008928:Mitochondria D063154:Mitochondrial Dynamics D000078722:PC-3 Cells D010744:Phosphoric Monoester Hydrolases D010766:Phosphorylation D013312:Stress, Physiological
inositol mitochondrial fission AMPK AMP IMPA1 energy stress glucose deprivation inosiotl sensor inositol/AMP ratio mitocondrial dynamics