Metabolic epistasis among apoptosis-inducing factor and the mitochondrial import factor CHCHD4

Hypomorphic mutation of apoptosis-inducing factor (AIF) in the whole body or organ-specific knockout of AIF compromises the activity of respiratory chain complexes I and IV, as it confers resistance to obesity and diabetes induced by high-fat diet. The mitochondrial defect induced by AIF deficiency can be explained by reduced AIF-dependent mitochondrial import of CHCHD4, which in turn is required for optimal import and assembly of respiratory chain complexes. Here we show that, as compared to wild type control littermates, mice with a heterozygous knockout of CHCHD4 exhibit reduced weight gain when fed with a Western style high-fat diet. This finding suggests widespread metabolic epistasis among AIF and CHCHD4. Targeting either of these proteins or their functional interaction might constitute a novel strategy to combat obesity.