Re-routing metabolism by the mitochondrial pyruvate carrier inhibitor MSDC-0160 attenuates neurodegeneration in a rat model of Parkinson’s disease

Abstract

Background: A growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinson's disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. Methods: We investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics. Results: MSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation and glutamate oxidation to satisfy energy needs and maintain energy homeostasis. Conclusion: MSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism. Keywords: Parkinson's disease, Neuroprotection, Mitochondrial pyruvate carrier, Energy metabolism

Metabolic Mechanisms Connecting Alzheimer’s and Parkinson’s Diseases: Potential Avenues for Novel Therapeutic Approaches

“…In further support of the importance of pyruvate metabolism in affecting PD pathology, Mallet et al (2022) have recently demonstrated that treatment with MSDC-0160 treatment improved motor behavior, decreased dopaminergic denervation, and reduced mTOR activity and neuroinflammation in the unilateral 6-OHDA rat model of PD. Metabolomic analysis indicated that reprogramming pyruvate metabolism increased ketogenesis, beta oxidation and glutamate oxidation and that multiple downstream pathways were likely involved in the beneficial effects.…”

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission

“…Understanding the metabolic plasticity of brain function in molecular detail has profound clinical implications for human physiology. Indeed, metabolic reprograming through MPC inhibition has emerged as an insulin sensitizing strategy for treatment of type II diabetes and has been shown to attenuate neurodegeneration in some Parkinson's disease models 19,20 . Given our finding that mitochondrial pyruvate uptake regulates synaptic transmission, it is critical to elucidate the short-term or long-term effects of MPC-modulating drugs on cognitive function in healthy individuals and patients suffering from metabolic and neurodegenerative diseases.…”

“…The physiological importance of MPC is further highlighted by its implication in several human pathologies, including cancer, cardiac hypertrophy, diabetes, and microcephaly 18 . Furthermore, there is also growing interest in targeting MPC for treatment of neurological disorders such as Parkinson's disease 19,20 . However, few studies have examined MPC function in the nervous system 21,22 , particularly in the metabolic control of synaptic transmission.…”