Metformin protects cells from mutant huntingtin toxicity through activation of AMPK and modulation of mitochondrial dynamics
Open accessAbstract
Huntington's disease (HD) is a devastating neurodegenerative disease caused by the pathological elongation of the CAG repeats in the huntingtin gene. Caloric restriction (CR) has been the most reproducible environmental intervention to improve health and prolong life span. We have demonstrated that CR delayed onset and slowed disease progression in a mouse model of HD. Metformin, an antidiabetic drug, mimics CR by acting on cell metabolism at multiple levels. Long-term administration of metformin improved health and life span in mice. In this study, we showed that metformin rescued cells from mutant huntingtin (HTT)-induced toxicity, as indicated by reduced lactate dehydrogenase (LDH) release from cells and preserved ATP levels in cells expressing mutant HTT. Further mechanistic study indicated that metformin activated AMP-activated protein kinase (AMPK) and that inhibition of AMPK activation reduced its protective effects on mutant HTT toxicity, suggesting that AMPK mediates the protection of metformin in HD cells. Furthermore, metformin treatment prevented mitochondrial membrane depolarization and excess fission and modulated the disturbed mitochondrial dynamics in HD cells. We confirmed that metformin crossed the blood-brain barrier after oral administration and activated AMPK in the mouse brain. Our results urge further evaluation of the clinical potential for use of metformin in HD treatment.
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Metformin-dependent AMPK activation protects mitochondria in Huntington's disease by affecting mitochondrial dynamics.
“metformin-dependent AMPK activation has recently demonstrated protection of mitochondria in huntington's disease by affecting mitochondrial dynamics (Jin et al., 2016).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Jin et al., 2016
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- Authors
- Jin, J., Gu, H., Anders, N. M., Ren, T., Jiang, M., Tao, M., Peng, Q., Rudek, M. A., & Duan, W.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Duan, Wenzhen
- Venue
- NeuroMolecular Medicine
- Published
- 2016-05-25
- Volume
- 18
- Issue
- 4
- Pages
- 581-592
- ISSN
- 1535-1084 (ISSN-L)
- 1559-1174
- PMC
- PMC5112128
- OpenAlex
- W2407471740
- Cited by
- 50
- References
- 30
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 7 · 2019: 5 · 2018: 7 · 2017: 3 · 2016: 2
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroMolecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS082338)
- National Cancer Institute (CA006973)
- National Center for Advancing Translational Sciences (TR001079)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- metformin, Huntington's disease, AMPK activation, mitochondrial dynamics, mitochondrial fission, mitochondrial depolarization, blood-brain barrier, neuroprotection, drug repurposing
- MeSH terms
- Huntingtin Protein, Animals, Disease Models, Animal, Enzyme Activation, Huntington Disease, Metformin, Mitochondria, Neuroprotective Agents, Mice, AMP-Activated Protein Kinases, Mitochondrial Dynamics
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