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

TitleMetformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria.
Publication TypeJournal Article
Year of Publication2020
AuthorsMor, DE, Sohrabi, S, Kaletsky, R, Keyes, W, Tartici, A, Kalia, V, Miller, GW, Murphy, CT
JournalProc Natl Acad Sci U S A
Volume117
Issue42
Pagination26438-26447
Date Published2020 10 20
ISSN1091-6490
Abstract

<p>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 and the neurodegenerative movement disorder Parkinson's disease (PD). RNAi-mediated knockdown of 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 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 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.</p>

DOI10.1073/pnas.2009838117
Alternate JournalProc Natl Acad Sci U S A
PubMed ID33024014
PubMed Central IDPMC7585014
Grant ListU2C ES030163 / ES / NIEHS NIH HHS / United States
P40 OD010440 / OD / NIH HHS / United States
F32 AG062036 / AG / NIA NIH HHS / United States
R01 ES023839 / ES / NIEHS NIH HHS / United States
DP1 GM119167 / GM / NIGMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States