TSG101 negatively regulates mitochondrial biogenesis in axons.
TSG101 negatively regulates mitochondrial biogenesis in axons.
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TSG101负性调节轴突线粒体的生物发生。
DOI：
10.1073/pnas.2018770118
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发表时间：
2021-05-18
影响因子：
11.1
通讯作者：
Freeman MR
中科院分区：
文献类型：
--
作者：
Lin TH;Bis-Brewer DM;Sheehan AE;Townsend LN;Maddison DC;Züchner S;Smith GA;Freeman MR
线粒体功能障碍与许多年龄依赖性神经退行性疾病如帕金森病和阿尔茨海默病有关，但了解神经元如何在体内维持功能性线粒体池在整个轴突中的足够密度和位置仍然是个谜。通过无偏的体内正向遗传筛选，我们确定了转运组分TSG 101所需的内体分选复合物，作为神经元中线粒体数量和大小的调节剂，并为将TSG 101作为线粒体生物发生的负调节剂提供了证据。我们进一步发现，TSG 101并不有助于Parkin/Pink 1介导的线粒体自噬，并发现宏观自噬调节剂ATG 1和ATG 6是轴突线粒体数量调节的关键。通过体内筛选，有可能解开轴突线粒体维持的可翻译机制。线粒体功能障碍与神经退行性疾病和特别容易变性的轴突之间存在密切联系，但线粒体如何维持在轴突中以支持其生理功能仍然不清楚。在体内正向遗传筛选突变体改变轴突线粒体，我们确定了tsg 101。tsg 101突变的神经元表现出线粒体数量增加和线粒体大小减少。TSG 101最为人所知的是作为转运所需的内体分选复合物（ESCRT）复合物的组分;然而，大多数其他ESCRT组分的丢失并不影响线粒体数量或大小，这表明TSG 101以非规范的、ESCRT独立的方式调节线粒体生物学。TSG 101突变体表型不是由线粒体自噬缺乏引起的，我们发现自噬阻断仅对细胞体中的线粒体有害，认为线粒体自噬和自噬对于轴突中线粒体数量的调节是有害的。有趣的是，TSG 101线粒体表型反而是由PGC-1 β/Nrf 2依赖性线粒体生物合成的激活引起的，这是mTOR独立的和TFEB依赖的，并且需要线粒体分裂-融合机制。我们的工作确定了TSG 101在抑制线粒体生物合成中的作用，这对于维持轴突隔室中线粒体数量和大小至关重要。
Mitochondrial dysfunction has been associated with many age-dependent neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease, yet understanding how a neuron maintains a pool of functional mitochondria in sufficient density and location throughout axons in vivo still remains enigmatic. Through an unbiased in vivo forward genetic screen, we identified an endosomal sorting complexes required for transport component, TSG101, as a modulator of mitochondrial number and size in neurons and provide evidence to place TSG101 as a negative regulator of mitochondrial biogenesis. We further find that TSG101 does not contribute to Parkin/Pink1-mediated mitophagy and discovered that macroautophagy regulators ATG1 and ATG6 are dispensable in axonal mitochondrial number regulation. Through in vivo screening, it is possible to unravel translatable mechanisms of axonal mitochondrial maintenance. There is a tight association between mitochondrial dysfunction and neurodegenerative diseases and axons that are particularly vulnerable to degeneration, but how mitochondria are maintained in axons to support their physiology remains poorly defined. In an in vivo forward genetic screen for mutants altering axonal mitochondria, we identified tsg101. Neurons mutant for tsg101 exhibited an increase in mitochondrial number and decrease in mitochondrial size. TSG101 is best known as a component of the endosomal sorting complexes required for transport (ESCRT) complexes; however, loss of most other ESCRT components did not affect mitochondrial numbers or size, suggesting TSG101 regulates mitochondrial biology in a noncanonical, ESCRT-independent manner. The TSG101-mutant phenotype was not caused by lack of mitophagy, and we found that autophagy blockade was detrimental only to the mitochondria in the cell bodies, arguing mitophagy and autophagy are dispensable for the regulation of mitochondria number in axons. Interestingly, TSG101 mitochondrial phenotypes were instead caused by activation of PGC-1ɑ/Nrf2-dependent mitochondrial biogenesis, which was mTOR independent and TFEB dependent and required the mitochondrial fission–fusion machinery. Our work identifies a role for TSG101 in inhibiting mitochondrial biogenesis, which is essential for the maintenance of mitochondrial numbers and sizes, in the axonal compartment.
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影响因子：
56.9
作者：
He, L;Lu, XY;Gunn, TM
通讯作者：
Gunn, TM
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
16.6
作者：
Lobas, Mark A.;Tao, Rongkun;Khakh, Baljit S.
通讯作者：
Khakh, Baljit S.
DOI：
10.1083/jcb.201801044
发表时间：
2018-05-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee JJ;Sanchez-Martinez A;Martinez Zarate A;Benincá C;Mayor U;Clague MJ;Whitworth AJ
通讯作者：
Whitworth AJ
影响因子：
30.8
作者：
Fleury, C;Neverova, M;Warden, CH
通讯作者：
Warden, CH