Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.
| dc.contributor.author | Hsu, Che-Chia | |
| dc.contributor.author | Zhang, Xian | |
| dc.contributor.author | Wang, Guihua | |
| dc.contributor.author | Zhang, Weina | |
| dc.contributor.author | Cai, Zhen | |
| dc.contributor.author | Pan, Bo-Syong | |
| dc.contributor.author | Gu, Haiwei | |
| dc.contributor.author | Xu, Chuan | |
| dc.contributor.author | Jin, Guoxiang | |
| dc.contributor.author | Xu, Xiangshang | |
| dc.contributor.author | Manne, Rajesh Kumar | |
| dc.contributor.author | Jin, Yan | |
| dc.contributor.author | Yan, Wei | |
| dc.contributor.author | Shao, Jingwei | |
| dc.contributor.author | Chen, Tingjin | |
| dc.contributor.author | Lin, Emily | |
| dc.contributor.author | Ketkar, Amit | |
| dc.contributor.author | Eoff, Robert | |
| dc.contributor.author | Xu, Zhi-Gang | |
| dc.contributor.author | Chen, Zhong-Zhu | |
| dc.contributor.author | Li, Hong-Yu | |
| dc.contributor.author | Lin, Hui-Kuan | |
| dc.date.accessioned | 2024-06-10T19:54:00Z | |
| dc.date.available | 2024-06-10T19:54:00Z | |
| dc.date.issued | 2021-09 | |
| dc.description.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. | |
| dc.identifier | S1097-2765(21)00692-4 | |
| dc.identifier.issn | 1097-2765 | |
| dc.identifier.issn | 1097-4164 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | Elsevier BV | |
| dc.relation.ispartof | Molecular cell | |
| dc.relation.isversionof | 10.1016/j.molcel.2021.08.025 | |
| dc.rights.uri | ||
| dc.subject | Cell Line | |
| dc.subject | Mitochondria | |
| dc.subject | Animals | |
| dc.subject | Mice, Inbred C57BL | |
| dc.subject | Mice, Knockout | |
| dc.subject | Humans | |
| dc.subject | Mice | |
| dc.subject | Inositol | |
| dc.subject | Phosphoric Monoester Hydrolases | |
| dc.subject | Phosphorylation | |
| dc.subject | Male | |
| dc.subject | Stress, Physiological | |
| dc.subject | AMP-Activated Protein Kinases | |
| dc.subject | Mitochondrial Dynamics | |
| dc.subject | PC-3 Cells | |
| dc.title | Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Hsu, Che-Chia|0000-0001-5630-5207 | |
| duke.contributor.orcid | Manne, Rajesh Kumar|0000-0002-2393-1348 | |
| pubs.begin-page | 3803 | |
| pubs.end-page | 3819.e7 | |
| pubs.issue | 18 | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Staff | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Pharmacology & Cancer Biology | |
| pubs.organisational-group | Pathology | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.publication-status | Published | |
| pubs.volume | 81 |
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