analyzing-oxygen-consumption-rate-primary-cultured-mouse-neonatal

Analyzing Oxygen Consumption Rate in Primary Cultured Mouse Neonatal Cardiomyocytes Using an Extracellular Flux Analyzer

Mitochondria and oxidative metabolism are critical for maintaining cardiac muscle function. Research has shown that mitochondrial dysfunction is an ...

University of California San Diego

For many years research in Parkinson's disease (PD) has linked mitochondrial dysfunction with the characteristic loss of dopaminergic neurons of the substantia nigra, accumulation of cytoplasmic inclusions termed Lewy bodies, and motor dysfunction (Henchcliffe & Beal, 2008). The most compelling connection is that Parkinsonism can be observed in both humans and animals following exposure to inhibitors of complex I of the electron transport chain (Betarbet et al, 2002).

In a flurry of PINK, mitochondrial bioenergetics takes a leading role in Parkinson's disease.

Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility. Rather, MPC inhibition rewires mitochondrial substrate metabolism to preferentially increase reliance on glutamate to fuel energetics and anaplerosis. Mobilizing the neuronal glutamate pool for oxidation decreases the quantity of glutamate released upon depolarization and, in turn, limits the positive-feedback cascade of excitotoxic neuronal injury. The finding links mitochondrial pyruvate metabolism to glutamatergic neurotransmission and establishes the MPC as a therapeutic target to treat neurodegenerative diseases characterized by excitotoxicity.

Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.

Recent studies indicate that glucose metabolism is altered in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Hexokinases (HKs) catalyse the first step in glucose metabolism, and HK2 constitutes the principal HK inducible isoform. We hypothesise that HK2 contributes to the synovial lining hypertrophy and plays a critical role in bone and cartilage damage.

Article	Year
In a flurry of PINK, mitochondrial bioenergetics takes a leading role in Parkinson's disease. EMBO molecular medicine\| PubMed ID: 20049706	2009
Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death. The Journal of cell biology\| PubMed ID: 28254829	2017
Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis. Annals of the rheumatic diseases\| PubMed ID: 30061164	2018

Anne N. Murphy

Biography

JoVE Journal Publications

Other Publications