Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 20, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2018770118
Keywords
mitochondria; mitochondrial biogenesis; ESCRT; TSG101; neurodegeneration
Categories
Funding
- NIH R21 [NS098364]
- Medical Research Council Momentum Award [MC_PC_16030/1]
- NIH [RO1 NS059991]
- UK Dementia Research Institute, Cardiff University
- Oregon Health AMP
- Science University
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This study found that TSG101 inhibits mitochondrial biogenesis in axons, which is crucial for maintaining mitochondrial numbers and sizes.
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 tsg707. Neurons mutant for tsg707 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-1alpha/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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