Somatic mitochondria! mutations in the mitochondria! genome occur more readily than in nuclear DMA and accumulate over time and with increasing age, leading to a decline in mitochondrial bioenergetic function. Mitochondrial DNA mutations have also been reported in patients undergoing hemodialysis. Common mechanisms such as oxidative stress and cytokine dysregulation may be responsible for mitochondrial injury in both aging and uremia. Mitochondrial DNA mutations have been reported in a variety of inherited neuromuscular diseases, diabetes, atherosclerosis, and age-related neurodegenerative disease. Mitochondria play an important role in heme synthesis, intracellular iron metabolism and erythropoietin response. Both aging and declining kidney function are strongly associated with the """"""""anemia of chronic disease"""""""" a condition where inflammation and reticuloendothelial iron transport blockade are believed to be fundamental. The central hypothesis driving this proposal is that mitochondrial injury and dysfunction is associated with the anemia of chronic disease among elderly patients with chronic kidney disease, and somatic mitochondrial mutations may be a genomic biomarker of this relationship. This hypothesis will be addressed by a case-control study, with patients drawn from the Kidney Disease and Hypertension Clinic at the Tufts-New England Medical Center. Somatic mitochondrial mutations will be genotyped by highthroughput techniques and mitochodrial membrane potential and oxygen consumption will be measured to assess mitochondrial function. Anemia will be completely characterized and clinical and intermediate phenotypes of anemia of chronic disease including inflammatory biomarkers and markers of deranged cellular iron metabolism will be related to mitochondrial DNA mutations and dysfunction. The effects of increasing age and declining GFR will be evaluated in this analysis both individually and interactively. The results of the study will offer new insights into the relationship of mitochondrial injury and anemia and allow us to evaluate the usefulness of identifying mutations as a marker of injury. There are several therapeutic measures that are known to improve mitochondrial function and biogenesis which may be potentially useful treatments for anemia of chronic disease among elderly patients with declining kidney function. ? ? ?
