Mitochondrial Genomic and Functional Differences between HSRA and ACI Rats Implicate Metabolism in Nephron Deficit

A reduced nephron endowment at birth is a strong determinant of future cardiovascular and renal disease risk. The HSRA rat, which develops with a solitary kidney (SK) ~75% of the time, provides a unique model to investigate developmental mechanisms contributing to nephron deficiency. Of the eight progenitor strains that comprise the HSRA, only the ACI rat exhibits a similar phenotype, albeit at a much lower incidence (~10%), suggesting that additional genetic modifiers exist within the HSRA. F1 crosses demonstrated that the incidence of SK follows maternal mitochondrial lineage such that F1-HSRAmito offspring display a SK incidence similar to HSRA, whereas F1-ACImito offspring are similar to ACI. The HSRA carries the Brown Norway mitochondrial genome, which is phylogenetically distinct from the ACI mitochondria. Whole genome sequencing identified 93 variants between HSRA and ACI mtDNA, with 10 predicted to have moderate functional effects in genes encoding components of Complex I (NADH dehydrogenase), Complex IV (cytochrome c oxidase), and ATP synthase. Mitochondrial function was evaluated in kidneys from aged male, two-kidney HSRA and ACI rats (n=4 per group) using high-resolution respirometry (Oroboros O2k). Complex-specific activity, reactive oxygen species (ROS) production, and citrate synthase activity were quantified by the UMMC Mitochondrial Research Core. HSRA kidneys exhibited a significant reduction in Complex II-driven respiration (p< 0.05), while ROS trended toward an increase and citrate synthase activity toward a decrease. Additional studies are planned to more comprehensively evaluate mitochondrial functional differences between the HSRA and ACI. These preliminary findings are consistent with predicted functional impacts of the identified mtDNA variants on oxidative phosphorylation. Single nuclei RNA sequencing performed during nephrogenesis identified dysregulation of Zc3h10, a mitochondrial biogenesis regulator, which suggests that mitochondrial and nuclear encoded mitochondrial genes may act as a modifier of developmental programming in the HSRA rat and contribute to impaired kidney development and long-term cardiovascular risk. This work was supported by R01HL137673 (MRG). The work performed through the UMMC Molecular and Genomics Facility is supported, in part, by funds from the NIGMS, including the Molecular Center of Health and Disease (P20GM144041), Mississippi INBRE (P20GM103476) and Obesity, Cardiorenal and Metabolic Diseases- COBRE (P30GM149404). The work performed through the UMMC Mitochondrial Research Core is supported by the NIGMS (P20GM121334). 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.