Mitochondrial dysfunction in acute kidney injury and sex-specific implications.

The kidney is one of the most energy-demanding organs in the human body, and the maintenance of mitochondrial homeostasis is central to kidney function. Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to the pathogenesis of AKI, from decreased ATP production, to enhanced mitochondrial oxidative stress, cell necrosis and apoptosis. Accumulating evidence suggests sexual dimorphism in the response to AKI with males demonstrating greater risk for developing ischemia-reperfusion and sepsis-induced kidney injury. In contrast, females may be more susceptible to nephrotoxic-AKI. There are important sex-related differences in mitochondrial respiration, biogenesis and dynamics that likely contribute to the observed sexual dimorphism in AKI. Sex hormones mediate many of these differences with multiple preclinical studies demonstrating the renoprotective actions of estrogen in many rodent models of AKI. Estrogenic control of mitochondrial biogenesis, function and reactive oxygen species (ROS) generation is discussed. Furthermore, the potential role for sex chromosomes in mediating sex differences in AKI is examined. Novel animal models such as the "four core genotypes" (FCG) mouse model provide us with important tools to study sex chromosome effects in kidney health and disease. By understanding the influences of sexual dimorphism or sex hormones on mitochondrial homeostasis and disease manifestations, we may be able to identify novel therapeutic targets and improve existing treatment options for AKI.