RRC ID 70766
Author Lin TH, Bis-Brewer DM, Sheehan AE, Townsend LN, Maddison DC, Züchner S, Smith GA, Freeman MR.
Title TSG101 negatively regulates mitochondrial biogenesis in axons.
Journal Proc Natl Acad Sci U S A
Abstract 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.
Volume 118(20)
Published 2021-5-18
DOI 10.1073/pnas.2018770118
PII 2018770118
PMID 33972422
PMC PMC8157921
MeSH Animals Animals, Genetically Modified Axons / metabolism* Cytoskeletal Proteins / genetics Cytoskeletal Proteins / metabolism DNA-Binding Proteins / genetics* DNA-Binding Proteins / metabolism Drosophila Proteins / genetics Drosophila Proteins / metabolism Drosophila melanogaster / genetics* Drosophila melanogaster / metabolism Endosomal Sorting Complexes Required for Transport / genetics* Endosomal Sorting Complexes Required for Transport / metabolism Female GTP-Binding Proteins / genetics GTP-Binding Proteins / metabolism Humans Male Mitochondria / genetics* Mitochondria / metabolism Mitochondrial Dynamics / genetics Mitophagy / genetics Mutation NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism Neurons / cytology Neurons / metabolism Organelle Biogenesis* Transcription Factors / genetics* Transcription Factors / metabolism
IF 9.412
Drosophila DGRC#140993