Mitochondrial hyperactivity as a potential therapeutic target in Parkinson’s disease

Abstract

Mitochondrial dysfunction is thought to contribute to neurodegeneration in Parkinson’s disease (PD), yet the cellular events that lead to mitochondrial disruption remain unclear. Post-mortem studies of PD patient brains and the use of complex I inhibitors to model the disease previously suggested a reduction in mitochondrial activity as a causative factor in PD, but this may represent an endpoint in the disease process. In our recent studies, we identified a novel link between branched-chain amino acid metabolism and PD, and uncovered mitochondrial hyperactivity as a potential alternative mechanism of PD pathogenesis. Increased mitochondrial activity may occur in a subset of PD patients, or may be a more common early event that precedes the ultimate loss of mitochondrial function. Therefore, it may be that any imbalance in mitochondrial activity, either increased or decreased, could cause a loss of mitochondrial homeostasis that leads to disease. An effective therapeutic strategy may be to target specific imbalances in activity at selective stages of PD or in specific patients, with any efforts to reduce mitochondrial activity constituting a surprising new avenue for PD treatment.

GAIT-GM integrative cross-omics analyses reveal cholinergic defects in a C. elegans model of Parkinson’s disease

“…Also consistent with previous findings was the positive correlation between L-valine and the oxidative phosphorylation pathway, since bcat-1 knockdown was reported to increase mitochondrial respiration (Mor et al, 2020). In addition, Lvaline was positively correlated with the phenylalanine, tyrosine and tryptophan biosynthesis pathway and negatively correlated with homologous recombination, entirely consistent with previously identified upregulation and downregulation of these pathways, respectively, in bcat-1(RNAi) worms (Mor et al, 2020). In summary, integrative results involving L-valine recapitulated previous observations and provided confidence on the power of the GAIT-GM approach to recover meaningful biological insights.…”

“…Several of these modules consisted of metabolites related to BCAA metabolism, including L-valine (Module 6), succinyl-CoA (Module 3), and thiamin diphosphate (Module 1). sPLS analysis of Module 6 revealed a negative correlation between L-valine and the valine, leucine and isoleucine degradation pathway (Figure 2B), which is consistent with the known increase of BCAAs in the bcat-1 background (Mansfeld et al, 2015;Mor et al, 2020). Also consistent with previous findings was the positive correlation between L-valine and the oxidative phosphorylation pathway, since bcat-1 knockdown was reported to increase mitochondrial respiration (Mor et al, 2020).…”

“…sPLS analysis of Module 6 revealed a negative correlation between L-valine and the valine, leucine and isoleucine degradation pathway (Figure 2B), which is consistent with the known increase of BCAAs in the bcat-1 background (Mansfeld et al, 2015;Mor et al, 2020). Also consistent with previous findings was the positive correlation between L-valine and the oxidative phosphorylation pathway, since bcat-1 knockdown was reported to increase mitochondrial respiration (Mor et al, 2020). In addition, Lvaline was positively correlated with the phenylalanine, tyrosine and tryptophan biosynthesis pathway and negatively correlated with homologous recombination, entirely consistent with previously identified upregulation and downregulation of these pathways, respectively, in bcat-1(RNAi) worms (Mor et al, 2020).…”

“…While some gene and metabolite KEGG IDs did not have associated pathways, 79 metabolites were mapped to a total of 75 unique pathways, and 1187 genes mapped to a total of 115 unique pathways (Supplementary Figure 1). Pathways where both metabolites and genes were found included valine, leucine and isoleucine degradation; alanine, aspartate and glutamate metabolism; glycolysis / gluconeogenesis; and citrate cycle (TCA cycle), which recapitulates the pathway identification obtained at the separate analysis of these data (Mor et al, 2020).…”

Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

“…Recent evidence indicates that deficits in BCAA catabolism may increase mitochondrial activity levels early in PD neurons. The resulting oxidative damage may drive the ultimate loss of mitochondrial function, eventually leading to neuronal cell death [ 262 ]. Remarkably, branched-chain amino transferase 1 (BCAT1) has been identified as a new player in PD pathogenesis [ 263 ].…”