Kidney function declines with advancing age and mitochondria have been implicated. In the present study we have examined the integrated function of mitochondria isolated from kidneys of 6- and 24-month-old Fischer 344 rats. OXPHOS (oxidative phosphorylation) of intact mitochondria and cytochrome c oxidase activity in permeabilized mitochondria were determined with polarographic assays. The activities of the ETC (electron transport chain) complexes and the cytochrome content in solubilized mitochondria were measured using spectrophotometric methods. The respiratory complexes were evaluated with blue native gel electrophoresis. Mitochondrial preparations were evaluated by immunoblotting for cytochrome c, Smac/Diablo and VDAC (voltage-dependent anion channel). Mitochondrial morphology was examined by electron microscopy. OXPHOS of mitochondria isolated from 24-month-old animals was decreased 15–25% with complexes I, II, III and IV, and fatty acid substrates. The electron microscopic appearance of mitochondria, the activity of the ETC complexes and the protein abundance of individual complexes and supercomplexes were unchanged. The content of cytochrome c was decreased by 37% in aged mitochondria, as determined by spectrophotometric methods and confirmed with immunoblotting. Polarographic determination of cytochrome c oxidase activity with endogenous cytochrome c demonstrated a 23% reduction in aged mitochondria, which was corrected with the addition of exogenous cytochrome c. Renal mitochondrial OXPHOS decreased with aging in the Fischer 344 rat. Decreased mitochondrial cytochrome c content is a major factor contributing to the OXPHOS defect of mitochondria isolated from kidneys of elderly animals.

Recessive mutations in XPNPEP3, encoding a mitochondrial x-prolyl aminopeptidase, have been identified in families with a rare hereditary tubulointerstitial kidney disease. The yeast ortholog of XPNPEP3, Icp55p, participates in the proteolytic processing and stabilization of mitochondrial proteins and its deletion accelerates the degradation of its protein targets. We used icp55 deletion strains of S. cerevisiae to model loss of XPNPEP3 enzymatic function and study its phenotypic consequences on mitochondrial function. We found that Icp55p is not required for respiratory competence; however, compared to controls deletion strains had reduced mitochondrial oxygen consumption when grown in glucose containing media. The reduced mitochondrial respiration of icp55 deletion strains in glucose media requires the mitochondrial peptide transporter, Mdl1p, and was corrected by Tor1p inhibition with rapamycin. Under similar growth conditions the abundance of the mitochondrial ATP synthase complex was decreased in the icp55 deletion strain and was corrected by concurrent deletion of tor1. The icp55 deletion strain demonstrated an increased chronological lifespan and decreased reactive oxygen species. These changes were additive to similar changes known to occur in tor1 deletion strains suggesting independent mechanisms. Together, these results demonstrate that loss of Icp55p function reduces mitochondrial oxygen consumption and ATP synthase complex assembly in glucose media, while also promoting stress resistance, decreasing reactive oxygen species and increasing chronological lifespan through mechanisms that are distinct from decreased Tor1p activity.

Multiple ongoing, government-funded national efforts longitudinally collect health data and biospecimens for precision medicine research with ascertainment strategies increasingly emphasizing underrepresented groups in biomedical research. We surveyed chronic kidney disease patients from an academic, public integrated tertiary care system in Cleveland, Ohio, to examine local attitudes toward participation in large-scale government-funded studies. Responses (n = 103) indicate the majority (71%) would participate in a hypothetical national precision medicine cohort and were willing to send biospecimens to a national repository and share de-identified data, but <50% of respondents were willing to install a phone app to track personal data. The majority of participants (62%) indicated that return of research results was very important, and the majority (54%) also wanted all of their research-collected health and genetic data returned. Response patterns did not differ by race/ethnicity. Overall, we found high willingness to participate among this Cleveland patient population already participating in a local genetic study. These data suggest that despite common perceptions, subjects from communities traditionally underrepresented in genetic research will participate and agree to store samples and health data in repositories. Furthermore, most participants want return of research results, which will require a plan to provide these data in a secure, accessible, and understandable manner.

The genetic contribution to calcium metabolism is well recognized. Many of the proteins that contribute to calcium homeostasis through intestinal absorption, bone deposition and resorption, renal reabsorption and the molecules regulating these processes have been identified. Mutations in many of the genes coding for these proteins have been identified and often have clear clinical phenotypes. These mutations are generally rare with large effect sizes and a high degree of penetrance. As monogenetic diseases, they have a mendelian inheritance pattern and have been identified with traditional family-based linkage studies. A great deal of progress has been made in the understanding of the physiology of calcium metabolism; however, it remains an evolving field. The identification of the monogenetic etiology of disease has contributed greatly to our understanding of calcium handling and homeostasis. Transgenic animal models of these diseases continue to offer new insights into the mechanisms of calcium metabolism and its regulation. The purpose of this review is to briefly outline calcium metabolism focusing on the mechanisms of intestinal absorption and renal reabsorption as a framework to review the monogenic causes of dysregulated calcium metabolism.