Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy.
Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy.
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DOI：
10.1073/pnas.2025932118
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发表时间：
2021-09-14
影响因子：
11.1
通讯作者：
Yan Z
中科院分区：
文献类型：
--
作者：
Drake JC;Wilson RJ;Laker RC;Guan Y;Spaulding HR;Nichenko AS;Shen W;Shang H;Dorn MV;Huang K;Zhang M;Bandara AB;Brisendine MH;Kashatus JA;Sharma PR;Young A;Gautam J;Cao R;Wallrabe H;Chang PA;Wong M;Desjardins EM;Hawley SA;Christ GJ;Kashatus DF;Miller CL;Wolf MJ;Periasamy A;Steinberg GR;Hardie DG;Yan Z
在这里，我们提出了明确的证据，AMPK全酶与线粒体网（mitoAMPK）在多个小鼠组织的保护在人类骨骼肌和心脏的证据物理协会。我们证明，mitoAMPK激活不均匀的线粒体网状线粒体能量应激。最后，我们提出的证据表明，骨骼肌中的mitoAMPK的激活是必需的线粒体自噬。我们建议mitoAMPK响应线粒体微环境线索，通过线粒体质量控制来维持能量稳态。线粒体形成一个复杂的、相互连接的网状结构，通过生物发生、动态裂变、融合和线粒体自噬之间的协调来维持，这些协调是响应于各种线索而启动的，以维持能量稳态。这些构成线粒体质量控制的细胞事件具有显著的空间精确性，但对这种空间特异性的控制机制知之甚少。在此，我们证明了细胞生物能量传感器的特定亚型，5′ AMP活化蛋白激酶（AMPKα1/α2/β2/γ1），位于小鼠和人类各种组织的线粒体外膜上，称为mitoAMPK。mitoAMPK的激活在整个网状系统中响应于能量应激而变化，并且mitoAMPK活性的抑制减弱了体内骨骼肌中运动诱导的线粒体自噬。AMPK的线粒体库及其对线粒体质量控制的局部重要性的发现强调了体内感测细胞能量学的复杂性，其对靶向线粒体能量学用于疾病治疗具有意义。
Here, we present unequivocal evidence of physical association of AMPK holoenzymes with mitochondrial reticulum (mitoAMPK) across multiple mouse tissues with evidence of conservation in human skeletal muscle and heart. We demonstrate that mitoAMPK is activated heterogeneously across the mitochondrial reticulum by mitochondrial energetic stress. Finally, we present evidence that suggests activation of mitoAMPK in skeletal muscle is required for mitophagy. We propose that mitoAMPK responds to mitochondrial microenvironment cues to maintain energetic homeostasis through mitochondrial quality control. Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5′ AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.
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横纹肌肉中能量网络的亚细胞连接分析。
影响因子：
16.6
作者：
Bleck CKE;Kim Y;Willingham TB;Glancy B
通讯作者：
Glancy B
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X
影响因子：
4.3
作者：
Drake, Joshua C.;Laker, Rhianna C.;Yan, Zhen
通讯作者：
Yan, Zhen
影响因子：
5.3
作者：
Francis, Shimon P.;Krey, Jocelyn F.;Shin, Jung-Bum
通讯作者：
Shin, Jung-Bum