Although molecular approaches altering mitochondrial content have implied a direct relationship between mitochondrial bioenergetics and
insulin sensitivity, paradoxically, consumption of a high-fat (HF) diet increases mitochondrial content while inducing
insulin resistance. We hypothesized that despite the induction of mitochondrial biogenesis, consumption of an HF diet would impair mitochondrial
ADP sensitivity in skeletal muscle of mice and therefore manifest in
mitochondrial dysfunction in the presence of
ADP concentrations indicative of skeletal muscle biology. We found that HF consumption increased
mitochondrial protein expression; however, absolute mitochondrial respiration and
ADP sensitivity were impaired across a range of biologically relevant
ADP concentrations. In addition, HF consumption attenuated the ability of
ADP to suppress mitochondrial H2O2 emission, further suggesting impairments in
ADP sensitivity. The abundance of
ADP transport proteins were not altered, but the sensitivity to
carboxyatractyloside-mediated inhibition was attenuated after HF consumption, implicating alterations in
adenine nucleotide translocase (ANT)
ADP sensitivity in these observations. Moreover,
palmitoyl-CoA is known to inhibit ANT, and modeling intramuscular
palmitoyl-CoA concentrations that occur after HF consumption exacerbated the deficiency in
ADP sensitivity. Altogether, these data suggest that an HF diet induces
mitochondrial dysfunction secondary to an intrinsic impairment in mitochondrial
ADP sensitivity that is magnified by
palmitoyl-CoA.