Enhanced glycolysis and GSK3 inactivation promote brain metabolic adaptations following neuronal mitochondrial stress.

We analyzed early brain metabolic adaptations in response to mitochondrial dysfunction in a mouse model of mitochondrial encephalopathy with complex IV deficiency [neuron-specific COX10 knockout (KO)]. In this mouse model, the onset of the mitochondrial defect did not coincide with immediate cell death, suggesting early adaptive metabolic responses to compensate for the energetic deficit. Metabolomic analysis in the KO mice revealed increased levels of glycolytic and pentose phosphate pathway intermediates, amino acids and lysolipids. Glycolysis was modulated by enhanced activity of glycolytic enzymes, and not by their overexpression, suggesting the importance of post-translational modifications in the adaptive response. Glycogen synthase kinase 3 inactivation was the most upstream regulation identified, implying that it is a key event in this adaptive mechanism. Because neurons are thought not to rely on glycolysis for adenosine triphosphate production in normal conditions, our results indicate that neurons still maintain their ability to upregulate this pathway when under mitochondrial respiration stress.

What role does mitochondrial stress play in neurodegenerative diseases?

The essential need for mitochondrial function has been extensively shown to relate to neuronal health. Neurodegeneration and neurodegeneration-related diseases have been associated with multiple mitochondrial dysfunctions. This review highlights key findings related to commonly studied mitochondrial dysfunctions: imbalance of mitochondrial dynamics, mutations in the mitochondrial genome, excessive reactive oxygen species, and misfolded protein associations/interactions with the mitochondria. Future research in mitochondrial function will help elucidate complex neurodegenerative events while impacting both individual and societal health.