Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria

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

Research output: Contribution to journalArticlepeer-review

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). RNAimediated 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.

Original languageEnglish (US)
Pages (from-to)26438-26447
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number42
DOIs
StatePublished - Oct 20 2020

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Branched-chain amino acid metabolism
  • Caenorhabditis elegans
  • Metformin
  • Mitochondria
  • Parkinson's disease

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