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Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria

Author(s): Mor, Danielle E; Sohrabi, Salman; Kaletsky, Rachel; Keyes, William; Tartici, Alp; et al

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Abstract: Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferase <i>BCAT-1</i> and the neurodegenerative movement disorder Parkinson's disease (PD). RNAi-mediated knockdown of <i>Caenorhabditis elegans bcat-1</i> is known to recapitulate PD-like features, including progressive motor deficits and neurodegeneration with age, yet the underlying mechanisms have remained unknown. Using transcriptomic, metabolomic, and imaging approaches, we show here that <i>bcat-1</i> knockdown increases mitochondrial respiration and induces oxidative damage in neurons through mammalian target of rapamycin-independent mechanisms. Increased mitochondrial respiration, or "mitochondrial hyperactivity," is required for <i>bcat-1(RNAi)</i> neurotoxicity. Moreover, we show that post-disease-onset administration of the type 2 diabetes medication metformin reduces mitochondrial respiration to control levels and significantly improves both motor function and neuronal viability. Taken together, our findings suggest that mitochondrial hyperactivity may be an early event in the pathogenesis of PD, and that strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.
Publication Date: 6-Oct-2020
Citation: Mor, Danielle E, Sohrabi, Salman, Kaletsky, Rachel, Keyes, William, Tartici, Alp, Kalia, Vrinda, Miller, Gary W, Murphy, Coleen T. (2020). Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria.. Proceedings of the National Academy of Sciences of the United States of America, 117 (42), 26438 - 26447. doi:10.1073/pnas.2009838117
DOI: doi:10.1073/pnas.2009838117
ISSN: 0027-8424
EISSN: 1091-6490
Pages: 26438 - 26447
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Proceedings of the National Academy of Sciences of the United States of America
Version: Final published version. This is an open access article.

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