Cytosolic adaptation to mitochondria-induced proteostatic stress causes progressive muscle wasting.
Cytosolic adaptation to mitochondria-induced proteostatic stress causes progressive muscle wasting.
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DOI：
10.1016/j.isci.2021.103715
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发表时间：
2022-01-21
期刊：
影响因子：
5.8
通讯作者：
Chen XJ
中科院分区：
文献类型：
--
作者：
Wang X;Middleton FA;Tawil R;Chen XJ
线粒体功能障碍导致许多疾病中的肌肉萎缩，也可能在衰老过程中。其基本机制尚不清楚。我们通过适度过表达核编码的腺嘌呤核苷酸移位酶Ant 1产生了线粒体蛋白负载和进口不平衡的转基因小鼠。我们发现这些小鼠逐渐失去骨骼肌。Ant 1超载减少线粒体呼吸。有趣的是，它还诱导小的热休克蛋白和侵略样结构的胞质溶胶中，这表明增加的蛋白质抑制负担，由于积累的非进口线粒体前蛋白。Ant 1转基因肌肉的转录组通过抑制蛋白质合成和促进蛋白酶体功能、自噬和溶酶体扩增而急剧重塑以抵消蛋白抑制应激。这些蛋白质抑制适应共同减少蛋白质含量，从而减少肌纤维大小和肌肉质量。因此，肌肉萎缩可以作为适应Escherichia诱导的蛋白抑制应激的权衡而发生。这一发现可能有助于理解肌肉萎缩的机制，特别是在与Ant 1过表达相关的疾病中，包括面肩肱营养不良。Ant 1过表达导致进行性肌肉萎缩而不影响寿命Ant 1过载饱和线粒体蛋白输入途径导致mPOS肌肉对mPOS作出反应以抑制蛋白质的合成并增加蛋白质的周转对mPOS的慢性适应减少肌纤维大小和肌肉质量作为权衡生物科学;细胞生理学;细胞生物学;细胞生物学的功能方面
Mitochondrial dysfunction causes muscle wasting in many diseases and probably also during aging. The underlying mechanism is poorly understood. We generated transgenic mice with unbalanced mitochondrial protein loading and import, by moderately overexpressing the nuclear-encoded adenine nucleotide translocase, Ant1. We found that these mice progressively lose skeletal muscle. Ant1-overloading reduces mitochondrial respiration. Interestingly, it also induces small heat shock proteins and aggresome-like structures in the cytosol, suggesting increased proteostatic burden due to accumulation of unimported mitochondrial preproteins. The transcriptome of Ant1-transgenic muscles is drastically remodeled to counteract proteostatic stress, by repressing protein synthesis and promoting proteasomal function, autophagy, and lysosomal amplification. These proteostatic adaptations collectively reduce protein content thereby reducing myofiber size and muscle mass. Thus, muscle wasting can occur as a trade-off of adaptation to mitochondria-induced proteostatic stress. This finding could have implications for understanding the mechanism of muscle wasting, especially in diseases associated with Ant1 overexpression, including facioscapulohumeral dystrophy. Ant1 overexpression causes progressive muscle wasting without affecting lifespan ANT1 overloading saturates the mitochondrial protein import pathway to cause mPOS Muscle responds to mPOS to repress the synthesis and increase turnover of proteins Chronic adaptation to mPOS reduces myofiber size and muscle mass as a trade-off Biological sciences; Cellular physiology; Cell biology; Functional aspects of cell biology
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影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC
DOI：
10.1152/ajpendo.00010.2014
发表时间：
2014-08-01
影响因子：
5.1
作者：
Fox, Daniel K.;Ebert, Scott M.;Adams, Christopher M.
通讯作者：
Adams, Christopher M.
影响因子：
64.8
作者：
Gabellini, D;D'Antona, G;Tupler, R
通讯作者：
Tupler, R
影响因子：
4.8
作者：
Ebert, Scott M.;Dyle, Michael C.;Adams, Christopher M.
通讯作者：
Adams, Christopher M.
影响因子：
4.1
作者：
Brand, MD;Pakay, JL;Cornwall, EJ
通讯作者：
Cornwall, EJ