| First Author | Hsu CC | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 18 | Pages | 3803-3819.e7 |
| PubMed ID | 34547240 | Mgi Jnum | J:315845 |
| Mgi Id | MGI:6831148 | Doi | 10.1016/j.molcel.2021.08.025 |
| Citation | Hsu CC, et al. (2021) Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK. Mol Cell 81(18):3803-3819.e7 |
| abstractText | 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 AMPKgamma and competes with AMP for AMPKgamma 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 AMPKgamma for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission. |
