The kidney is a mitochondria-rich organ with regionally distinct metabolic demands, as the cortex and medulla differ in function, transport, and energy requirements. Importantly, sex differences in mitochondrial function are increasingly recognized as key contributors to renal disease development. Our studies in rodents suggest that male renal mitochondria exhibit higher respiration, although respiratory efficiency is higher in females. ROS production and substrate preference also differ between male and female mitochondria. However, these differences have not been defined in human kidneys, and the metabolic basis for sex-specific mitochondrial function remains uncharacterized. To address this gap, we hypothesized that mitochondrial metabolic profiles differ by sex and region in the human kidneys, independent of comorbidities. Targeted ‘omic analysis of mitochondria-related metabolites using the kidney cortex was performed. Kidney cortex and medulla from 8 male and 5 female human subjects, average age 54±3 years, were analyzed. A semi-automatic approach was used for the analysis of pathway-specific alterations. Metabolic profiles were generated using UHPLC-HRMS; 220 selected metabolites were identified in El-MAVEN using exact mass and retention time with an in-house library. MetaboAnalyst 6.0 was used for statistical analysis (cutoff fold change 0.5, p< 0.05). Steroid hormone levels were assessed using targeted LC–MS/MS. Statistical analysis was performed in Origin. Sex differences in mitochondrial metabolic pathways were most pronounced in the renal cortex, where females and males showed distinct alterations across amino acid, nucleotide, and one-carbon metabolic networks. In the cortex, males exhibited significantly lower activity in arginine biosynthesis (p< 0.001), pyrimidine metabolism (p< 0.001), alanine/aspartate/glutamate metabolism (p< 0.001), and folate-dependent one-carbon metabolism (p< 0.01). Additional pathways, including phenylalanine metabolism (p< 0.05) and glycine metabolism (p< 0.01), were also reduced in males, highlighting sex-specific differences in nitrogen balance, redox buffering, and mitochondrial substrate utilization. In the medulla, males demonstrated increased purine catabolism (p< 0.001) and decreased pyrimidine metabolism (p< 0.001), along with overlapping amino acid pathway alterations shared with the cortex. Supporting the sex hormones-driven basis of these differences, correlation analyses revealed significant associations between tissue estradiol and metabolic signatures including amino acids (phenylalanine, r=0.75), carbohydrate metabolites (trehalose/sucrose, r=−0.65; N-acetylglucosamine 1/6-phosphate, r=0.70; sucralose, r=0.83), and glycolytic intermediates (d-glyceraldehyde-3-phosphate, r=0.62; sn-glycerol-3-phosphate, r=0.61). Together, these findings indicate a clear region-specific sexual dimorphism in mitochondrial metabolism, with females exhibiting greater preservation of amino acid, nucleotide, and redox-supporting pathways in both cortex and medulla. Our data demonstrate that mitochondrial metabolism in the human kidney exhibits clear sex-specific signatures, particularly within the cortical region. The observed patterns suggest that sex hormones, specifically estrogen, may be key drivers of the recorded metabolic differences, shaping mitochondrial bioenergetic and biosynthetic profiles in male and female kidneys. Future studies will correlate these metabolic patterns with clinical and histopathological phenotypes to determine how sex-linked mitochondrial programs influence susceptibility to, and progression of, kidney injury. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Semenikhina et al. (Fri,) studied this question.
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