Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.
Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.
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DOI：
10.1016/j.molcel.2021.08.025
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发表时间：
2021-09-16
期刊：
影响因子：
16
通讯作者：
Lin HK
中科院分区：
文献类型：
--
作者：
Hsu CC;Zhang X;Wang G;Zhang W;Cai Z;Pan BS;Gu H;Xu C;Jin G;Xu X;Manne RK;Jin Y;Yan W;Shao J;Chen T;Lin E;Ketkar A;Eoff R;Xu ZG;Chen ZZ;Li HY;Lin HK
线粒体融合和分裂调控的线粒体动力学本质上维持线粒体的功能，线粒体功能的改变突显了各种人类疾病。在这里，我们表明，肌醇是一种关键的代谢物，直接限制AMPK依赖的线粒体分裂，独立于其作为磷脂酰肌醇生成前体的经典模式。IMPA1/2缺乏引起的肌醇减少引起AMPK激活和线粒体分裂，而不影响ATP水平，而肌醇积累则阻止依赖AMPK的线粒体分裂。代谢应激或线粒体损伤导致细胞和小鼠的肌醇下降，从而引发依赖AMPK的线粒体分裂。肌醇直接与AMPKγ结合，与AMP竞争AMPKγ结合，从而限制AMPK的激活和线粒体的分裂。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AMPK激活需要肌醇下降才能释放AMPKγ以与AMP结合的模型。因此，AMPK是一种肌醇传感器，其被肌醇灭活是限制线粒体分裂的一种机制。Hu等人的研究。证明肌醇通过与AMPKγ亚基直接结合，发挥内源性抑制作用，限制AMPK的激活和线粒体的分裂。AMP/肌醇和AMP/ATP比值是AMPK激活和线粒体分裂的关键决定因素。因此，AMPK是一种肌醇传感器，通过检测细胞中的肌醇梯度来协调线粒体的分裂。
Mitochondrial dynamics regulated by mitochondrial fusion and fission essentially 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, while 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 restricting AMPK activation and mitochondrial fission. Our study suggests that AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model where 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. 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 ratio 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.
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影响因子：
29
作者：
Gowans GJ;Hawley SA;Ross FA;Hardie DG
通讯作者：
Hardie DG
影响因子：
50.3
作者：
Carroll PA;Diolaiti D;McFerrin L;Gu H;Djukovic D;Du J;Cheng PF;Anderson S;Ulrich M;Hurley JB;Raftery D;Ayer DE;Eisenman RN
通讯作者：
Eisenman RN
影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
4.1
作者：
Goswami R;Bondoc JMG;Wheeler PR;Jafari A;Gonzalez T;Mehboob S;Movahedzadeh F
通讯作者：
Movahedzadeh F
DOI：
10.1073/pnas.96.15.8745
发表时间：
1999-07-20
影响因子：
11.1
作者：
Chalecka-Franaszek, E;Chuang, DM
通讯作者：
Chuang, DM