Mitochondrial Apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways

A variety of metabolic disorders are aggravated by obesity. Since mitochondria play key roles in various catabolic and anabolic reactions encompassing lipid metabolism, optimal functioning of mitochondria is critical in preventing various pathologies. Increased amounts of the apolipoprotein O /MIC26 were found in diabetic patients along with lipid accumulation in murine liver upon MIC26 expression. MIC26 is a MICOS complex constituent present in the mitochondrial inner membrane. The functional interplay between MIC26 and cellular metabolome is not understood. Therefore, we employed a multi-omics approach in WT and MIC26 knockout HepG2 cellular models in normoglycemic and hyperglycemic conditions, along with a variety of functional assays. We found that MIC26 is necessary for maintaining glycolysis and lipid metabolism via CPT1A along with cholesterol synthesis in a nutrient-dependent manner. MIC26 deletion led to metabolic rewiring of glutamine utilisation leading us to propose that mitochondrial ultrastructure and cellular metabolome are functionally interdependent. Overall design: The study included HepG2 WT and MIC26 KO cells cultured either in normoglycemic (N /LG) or hyperglycemic (H / HG) conditions for 3 weeks. RNA-seq. was performed.