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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. [Display omitted] • IMPA-derived inositol modulates mitochondrial fission • Inositol restricts aberrant AMPK activation and mitochondrial fission • Inositol decline leads to AMPK-dependent mitochondrial fission upon energy stress • Inositol binds directly to AMPKγ and competes with AMP for AMPKγ binding Hsu et al. demonstrate that inositol serves as an endogenous suppressor to limit AMPK activation and mitochondrial fission through its direct binding to the AMPKγ subunit. AMP/inositol and AMP/ATP ratios serve as critical determinants for AMPK activation and mitochondrial fission. AMPK is therefore an inositol sensor orchestrating mitochondrial fission by detecting the inositol gradient in cells. [ABSTRACT FROM AUTHOR]