Fig. 1

Attenuation of mitochondrial pyruvate transport by MSDC-0160 restores metabolic pathways in neurons and glial cells. a) MSDC-0160 slows the uptake of pyruvate into mitochondria by modulating the mitochondrial pyruvate carrier complex. This lowers the direct usage of pyruvate as a substrate for the tricyclic carboxylic acid cycle (TCA) and perhaps lowers the production of harmful reactive oxygen species (ROS); b) Different insults (MPP⁺, En1^−/+ and ɑ-synuclein overexpression) producing Parkinson-related pathophysiology in animal models result in neurodegenerative changes in neurons and induce reactive microglial cells. These responses involve relative activation of mTOR activity and changes in AKT activation. In sensitive neurons, this is associated with reduced autophagy and increased cell death. Similar changes in mTOR and AKT are observed in microglial cells correlating with increased inflammation including increases in inducible nitric oxide synthase and cytokine release. During the process of neurodegeneration, pathogen-associated and damage-associated pattern molecules (PAMPS and DAMPS) activate microglial cells resulting in the release of pro-inflammatory molecules; c) Attenuation of pyruvate uptake by MSDC-0160 has direct effects on both neurons and microglia counteracting the effects of the environmental and genetic insults. The attenuation of pyruvate uptake by mitochondria in multiple cell types changes the metabolic balance signals in a way that attenuates the activation of mTOR, while activating the autophagic pathway. The overall protection and recovery from the Parkinson-related pathophysiology involved direct effects on both neuronal and glial cells. The direct effects of MSDC-0160 on glial cells may also indirectly affect other cell types due to the release of pro-inflammatory cytokines. Inhibiting the mitochondrial pyruvate carrier complex via MSDC-0160 restores oxidative consumption in glial cells leading to downstream alterations in the mTOR signaling pathway and a consequent reduction of pro-inflammatory molecules. This metabolic rewiring alters the activation state of microglial cells which is beneficial for limiting the neurodegenerative process. The study of interactions between neuronal and glial cells, as well as cells within the central and peripheral nervous system may aid in understanding the impact of metabolic modulators on these processes and help in the design of clinical trials and novel drugs