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

Sofia Garcia, Amy Saldana-Caboverde, Mir Anwar, Ami Pravinkant Raval, Nadee Nissanka, Milena Pinto, Carlos Torres Moraes, Francisca Diaz

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)692-704
Number of pages13
JournalHuman molecular genetics
Volume31
Issue number5
DOIs
StatePublished - Mar 1 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Enhanced glycolysis and GSK3 inactivation promote brain metabolic adaptations following neuronal mitochondrial stress'. Together they form a unique fingerprint.

Cite this