Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA.
Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA.
Mol Cell. 2021 Sep 16;81(18):3803-3819.e7. doi: 10.1016/j.molcel.2021.08.025.
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.
线粒体的融合和分裂所调控的动态平衡维持着线粒体的功能，其改变是各种人类疾病的基础。在这里，我们表明肌醇是一种关键代谢物，可独立于其作为磷酸肌醇生成前体的经典模式，直接限制 AMPK 依赖性的线粒体分裂。IMPAl/2 缺乏导致肌醇减少会引发 AMPK 激活和线粒体分裂，而不影响 ATP 水平，而肌醇积累则可防止 AMPK 依赖性的线粒体分裂。代谢应激或线粒体损伤会导致细胞和小鼠中的肌醇减少，从而引发 AMPK 依赖性的线粒体分裂。肌醇直接与 AMPKγ 结合，并与 AMP 竞争 AMPKγ 的结合，从而限制了 AMPK 的激活和线粒体分裂。我们的研究表明，AMP/肌醇比值是 AMPK 激活的关键决定因素，并建立了一个模型，即 AMPK 的激活需要肌醇的减少来释放 AMPKγ 与 AMP 结合。因此，AMPK 是肌醇的传感器，其失活是限制线粒体分裂的一种机制。
