Polymerase Gamma Mutator (PolG) Mice Rely on Increased Glycolytic Flux for Energy Production

PolG mice have reduced mitochondrial oxidative capacity secondary to systemic mitochondrial dysfunction, and subsequently show exercise intolerance. While the deleterious effects on oxidative capacity in the PolG mice have been clearly documented, assessment of a compensatory increase in anaerobic capacity in PolG mice is lacking. Thus, we sought to delineate the extent of glycolysis/gluconeogensis as a means of energy production in the PolG mice. PolG and wild‐type (WT) littermates were sacrificed at 10 mths of age, and blood/tissues were harvested. Primary dermal fibroblasts were also isolated from the animals and used to measure basal/maximal glycolysis using the Glycolysis stress test (Seahorse Bioscience). PolG mice displayed higher respiratory exchange ratio (RER) values, coupled with 55% lower locomotor activity compared to littermate WT mice (P < 0.05). PolG mice displayed resting hypoglycemia (3.4 mM), concomitantly with lower glucose levels throughout the GTT test as compared to WT, ~3‐fold higher PFK content, and elevated plasma lactate levels (>10 mM)(all P < 0.05). In vitro experiments provide further proof that PolG derived dermal fibroblasts have an ~50% higher basal and maximal rate of glycolysis vs . WT control. It is likely that the higher lactate content serves as substrate for the Cori cycle to generate glucose in the liver via gluconeogenesis. Indeed the mRNA content of two important gluconeogenic liver enzymes, G6P and PEPCK, was increased by ~3‐4x fold in the POLG mice compared to WT. Lactic acidosis and hypoglycemia have been associated with poor prognosis in a variety of mitochondrial diseases, and the presence in the PolG animals is a novel finding that warrants further attention. Funded by CIHR.