Brain redox bioenergetics are determined by OXPHOS organization in neurons and astrocytes

Abstract

Energy and redox conservation in the brain requires a tight and complementary metabolic cooperation between distinct cell types. Neurons are highly dependent on mitochondrial oxidative (OXPHOS) metabolism for survival, whereas astrocytes are highly resistant to OXPHOS inhibition. A key factor of these phenotypes is PFKFB3, a glycolytic-promoting enzyme. We have shown that PFKFB3 is a substrate of the E3 ubiquitin ligase, APC/C-Cdh1. By degrading PFKFB3 protein, APC/C-Cdh1 physiologically down-regulates glycolysis in neurons. However, PFKFB3 over-expression in neurons causes serious metabolic and behavioral problems in vivo. Recently, we studied whether the organization of the mitochondrial respiratory chain (MRC) determines these specific metabolic programs of neurons and astrocytes. In astrocytes, most complex I (CI) is disassembled from supercomplexes (SCs) resulting in poor mitochondrial respiration but high reactive oxygen species (ROS) production. In contrast, neurons show CI mostly embedded into SCs resulting in efficient mitochondrial respiration and low ROS production. We conclude that MRC organization is key at dictating the bioenergetics shapes of neurons and astrocytes that impacts on ROS production, signaling processes and neurological disorders.