Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition
Open accessAbstract
In addition to key roles in embryonic neurogenesis and myelinogenesis, γ‐aminobutyric acid (GABA) serves as the primary inhibitory mammalian neurotransmitter. In yeast, we have identified a new role for GABA that augments activity of the pivotal kinase, Tor1. GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch9, the homolog of the mammalian kinase, S6K1, leading to oxidative stress, all of which can be mitigated by the Tor1 inhibitor, rapamycin. To confirm these processes in mammals, we examined the succinic semialdehyde dehydrogenase (SSADH)‐deficient mouse model that accumulates supraphysiological GABA in the central nervous system and other tissues. Mutant mice displayed increased mitochondrial numbers in the brain and liver, expected with a defect in mitophagy, and morphologically abnormal mitochondria. Administration of rapamycin to these mice reduced mTOR activity, reduced the elevated mitochondrial numbers, and normalized aberrant antioxidant levels. These results confirm a novel role for GABA in cell signaling and highlight potential pathomechanisms and treatments in various human pathologies, including SSADH deficiency, as well as other diseases characterized by elevated levels of GABA.
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Loss of SSADH function leads to an increased number of morphologically abnormal mitochondria in the brain.
“Loss of SSADH function leads to an increased number of morphologically abnormal mitochondria in the brain (Lakhani et al., 2014)”
From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Lakhani et al., 2014
The Results report increased mitochondrial numbers in the brains of SSADH-deficient mice, but the morphological differences measured by electron microscopy were in liver mitochondria. The Discussion likewise identifies larger mitochondria specifically in the liver; our copy does not establish that the brain mitochondria were morphologically abnormal. (LLM, conf=0.90)
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- Authors
- Lakhani, R., Vogel, K. R., Till, A., Liu, J., Burnett, S. F., Gibson, K. M., & Subramani, S.
- Affiliations
- University of California San Diego (US)
- Washington State University Spokane (US)
- Corresponding author
- Subramani, Suresh
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2014-02-27
- Volume
- 6
- Issue
- 4
- Pages
- 551-566
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3992080
- OpenAlex
- W2113033693
- Cited by
- 75
- References
- 1
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 2 · 2018: 8 · 2017: 5 · 2016: 11 · 2015: 7 · 2014: 3
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (GM 069373, HD 58553)
- SSADH Association
- DFG (Ti‐640 1‐1)
- San Diego Center for Systems Biology (GM 085764)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- GABA, selective autophagy, mitophagy, pexophagy, Sch9, mTOR inhibition, rapamycin, succinic semialdehyde dehydrogenase deficiency, oxidative stress, mitochondrial accumulation, yeast, GABA signaling
- MeSH terms
- Amino Acid Metabolism, Inborn Errors, Animals, Autophagy, Brain, Developmental Disabilities, gamma-Aminobutyric Acid, Humans, Liver, Mice, Knockout, Succinate-Semialdehyde Dehydrogenase, Mice, TOR Serine-Threonine Kinases
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