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Publication Detail

Title: Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria.

Authors: Mor, Danielle E; Sohrabi, Salman; Kaletsky, Rachel; Keyes, William; Tartici, Alp; Kalia, Vrinda; Miller, Gary W; Murphy, Coleen T

Published In Proc Natl Acad Sci U S A, (2020 10 20)

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 BCAT-1 and the neurodegenerative movement disorder Parkinson's disease (PD). RNAi-mediated knockdown of Caenorhabditis elegans bcat-1 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 bcat-1 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 bcat-1(RNAi) 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.

PubMed ID: 33024014 Exiting the NIEHS site

MeSH Terms: Amino Acids, Branched-Chain/metabolism; Amino Acids, Branched-Chain/physiology; Animals; Caenorhabditis elegans Proteins/metabolism; Caenorhabditis elegans/metabolism; Disease Models, Animal; Metformin/metabolism; Metformin/pharmacology*; Mitochondria/drug effects*; Neurons/drug effects; Parkinson Disease/drug therapy*; Parkinson Disease/metabolism; Phenotype

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