Data associated with 'Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria'
Mor, Danielle et al. (2020), Data associated with 'Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria', Dryad, Dataset, https://doi.org/10.5061/dryad.5mkkwh72q
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 C. elegans bcat-1 recapitulates 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 mTOR-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. Together, our findings suggest that mitochondrial hyperactivity may be an early event in PD pathogenesis, and strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.
High-resolution metabolomics data was generated using samples collected per the methods described in the manuscript. Files generated from the Thermo orbitrap instrument were extracted using the apLCMS and xMSanalyzer R packages. A feature was retained in the feature table if its intensity was 1.5 times that of the intensity in the associated bacterial blank sample and was present in at least 9 of the samples. Null (intensity = 0) values were replaced with the half the value of the minimum intensity of that feature.
The feature table has been filtered using bacterial blank samples and null values of intensity have been imputed.
National Institutes of Health, Award: NIGMS 5DP1GM119167
Glenn Foundation for Medical Research, Award: GMFR CNV1001899
National Institutes of Health, Award: NIEHS U2CES030163
National Institutes of Health, Award: NIEHS R01ES023839
National Institutes of Health, Award: NIA F32AG062036