TY - JOUR
T1 - Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria
AU - Mor, Danielle E.
AU - Sohrabi, Salman
AU - Kaletsky, Rachel
AU - Keyes, William
AU - Tartici, Alp
AU - Kalia, Vrinda
AU - Miller, Gary W.
AU - Murphy, Coleen T.
N1 - Funding Information:
We thank the C. elegans Genetics Center for strains (P40 OD010440), the Genomics Core Facility and Confocal Imaging Facility at Princeton University, Dr. Dean Jones and the Clinical Biomarkers Laboratory at Emory University, BioRender.com for model figure design software, and members of the C.T.M. lab for discussion. Strain UA44 was generously provided by G. Caldwell (University of Alabama). C.T.M. is the Director of the Glenn Center for Aging Research at Princeton and an HHMI-Simons Faculty Scholar. D.E.M. was supported by a Ruth L. Kirschstein National Research Service Award (NIA F32AG062036). Further support was provided by the NIH (NIEHS U2CES030163 and R01 ES023839, to G.W.M.; DP1 Pioneer Award NIGMS 5DP1GM119167, to C.T.M.) and the Glenn Foundation for Medical Research (CNV1001899, to C.T.M.).
Funding Information:
ACKNOWLEDGMENTS. We thank the C. elegans Genetics Center for strains (P40 OD010440), the Genomics Core Facility and Confocal Imaging Facility at Princeton University, Dr. Dean Jones and the Clinical Biomarkers Laboratory at Emory University, BioRender.com for model figure design software, and members of the C.T.M. lab for discussion. Strain UA44 was generously provided by G. Caldwell (University of Alabama). C.T.M. is the Director of the Glenn Center for Aging Research at Princeton and an HHMI-Simons Faculty Scholar. D.E.M. was supported by a Ruth L. Kirschstein National Research Service Award (NIA F32AG062036). Further support was provided by the NIH (NIEHS U2CES030163 and R01 ES023839, to G.W.M.; DP1 Pioneer Award NIGMS 5DP1GM119167, to C.T.M.) and the Glenn Foundation for Medical Research (CNV1001899, to C.T.M.).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/10/20
Y1 - 2020/10/20
N2 - 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.
AB - 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.
KW - Branched-chain amino acid metabolism
KW - Caenorhabditis elegans
KW - Metformin
KW - Mitochondria
KW - Parkinson's disease
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U2 - 10.1073/pnas.2009838117
DO - 10.1073/pnas.2009838117
M3 - Article
C2 - 33024014
AN - SCOPUS:85093851211
SN - 0027-8424
VL - 117
SP - 26438
EP - 26447
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
ER -