TSG101 negatively regulates mitochondrial biogenesis in axons

Lin, Tzu-Huai, Bis-Brewer, Dana M., Sheehan, Amy E., Townsend, Louise N., Maddison, Daniel C. ORCID: https://orcid.org/0000-0003-3038-1687, Züchner, Stephan, Smith, Gaynor A. ORCID: https://orcid.org/0000-0003-4332-8383 and Freeman, Marc R. 2021. TSG101 negatively regulates mitochondrial biogenesis in axons. Proceedings of the National Academy of Sciences 118 (20) , e2018770118. 10.1073/pnas.2018770118

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	This open access article is distributed under Creative Commons Attribution-NonCommercial�NoDerivatives License 4.0 (CC BY-NC-ND)
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	21 May 2021
Date of Acceptance:	5 April 2021
Last Modified:	10 Feb 2024 02:14
URI:	https://orca.cardiff.ac.uk/id/eprint/141516

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