Abstract
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.
Original language | English (US) |
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Pages (from-to) | 3803-3819.e7 |
Journal | Molecular Cell |
Volume | 81 |
Issue number | 18 |
DOIs | |
State | Published - Sep 16 2021 |
Externally published | Yes |
Keywords
- AMP
- AMPK
- IMPA1
- energy stress
- glucose deprivation
- inosiotl sensor
- inositol
- inositol/AMP ratio
- mitochondrial fission
- mitocondrial dynamics
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology