Mitochondrial Biology and Medicine

Abstract Since their discovery 30 years ago, mutations in mitochondrial genes causing defects in oxidative phosphorylation (OXPHOS) have emerged as among the most common inherited metabolic disorders. Mitochondrial dysfunction can result from mutations in the multicopy mitochondrial DNA (mtDNA) or in any of the approximately 1500 nuclear DNA (nDNA) encoded mitochondrial genes. Clinically relevant mtDNA variants include pathogenic mutations causing maternally inherited diseases, ancient functional polymorphisms, and developmental and somatic tissue mutations. Clinically relevant nDNA mutations can affect structural, assembly, metabolic, and biogenesis genes. Mitochondrial OXPHOS is also acutely sensitive to environmental factors such as temperature, altitude, calorie availability and demands, infections, and toxins. Bioenergetic adaptation to genetic and environmental variations can also occur through the epigenome and signal transduction pathways. Perturbations in this bioenergetics system biology are being implicated in a broad range of common diseases such as diabetes and metabolic syndrome, inflammatory problems, deafness and blindness, cardiac and muscle diseases, Leigh syndrome, autism, and Alzheimer and Parkinson diseases. The discovery of the mitochondrial etiology of both rare and common diseases has revealed new therapeutic targets. These include mitochondrial biogenesis, antioxidant and antiapoptotic drugs, various somatic mitochondrial gene therapy approaches, and the demonstration that nuclear transplantation can purge deleterious mtDNAs from the female germline.