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Updated: Nov 6, 2025
08:48
Author Spotlight: Decoding Mitochondrial Aging
Published on: June 30, 2023
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TSG101 negatively regulates mitochondrial biogenesis in axons
Tzu-Huai Lin1, Dana M Bis-Brewer2,3, Amy E Sheehan1
1Vollum Institute, Oregon Health & Science University, Portland, OR 97239.
Summary
TSG101 protein regulates mitochondrial biogenesis in axons, independent of its known ESCRT function. Loss of TSG101 leads to altered mitochondrial number and size, crucial for axonal health.
Area of Science:
- Neurobiology
- Cell Biology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is linked to neurodegenerative diseases.
- Axons are highly vulnerable to degeneration, but mitochondrial maintenance in axons is poorly understood.
Purpose of the Study:
- To investigate the mechanisms of mitochondrial maintenance in axons.
- To identify novel regulators of axonal mitochondrial dynamics.
Main Methods:
- In vivo forward genetic screen in neurons.
- Analysis of mitochondrial number and size in tsg101 mutants.
- Investigation of ESCRT complex, mitophagy, autophagy, and biogenesis pathways.
Main Results:
- Mutations in tsg101 altered mitochondrial number and size in axons.
- TSG101's role was noncanonical and ESCRT-independent.
- Mitochondrial phenotypes were due to PGC-1ɑ/Nrf2-dependent biogenesis, independent of mTOR, dependent on TFEB, and required fission-fusion machinery.
- Mitophagy and autophagy were dispensable for axonal mitochondrial regulation.
Conclusions:
- TSG101 inhibits mitochondrial biogenesis, essential for maintaining mitochondrial numbers and sizes in axons.
- This identifies a novel, noncanonical role for TSG101 in axonal mitochondrial homeostasis.
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