Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA have been implicated in a wide range of degenerative diseases. MtDNA base substitution and rearrangement mutations can cause myopathy, cardiomyopathy, ophthalmological defects, growth retardation, movement disorders, dementias, and diabetes. nDNA mutations can affect mtDNA replication and transcription, increase mtDNA mutations through defects in the adenine nucleotide translocator isoform 1 (ANT1), or cause Leigh's syndrome, as a result of defects in oxidative phosphorylation (OXPHOS) structural genes. Mouse models of mtDNA base substitution mutations have been created by introducing the mtDNA 16S rRNA chloramphenicol (CAP)-resistance mutation into the mouse female germline. This resulted in ophthalmological defects in chimeras and perinatal lethality resulting from myopathy and cardiomyopathy in mutant animals. Mouse models of mtDNA rearrangements have resulted in animals with myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the mouse nDNA mitochondrial transcription factor (Tfam) gene in the heart caused neonatal lethal cardiomyopathy, whereas its inactivation in the pancreatic beta-cells caused diabetes. Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. This suggests that multiple mtDNA deletion syndrome can be caused by increased ROS damage. The inactivation of the uncoupler protein genes (Ucp) 1-3 resulted in alterations in delta mu H+ and increased ROS production. Inactivation of the Ucp2 gene, which is expressed in the pancreatic beta-cells, resulted in increased islet ATP, increased serum insulin levels, and suppression of the diabetes of the ob/ob mouse genotype. Transgenic mice with altered beta-cell ATP-sensitive K+ channels (KATP) also developed diabetes. Mutational inactivation of the mitochondrial antioxidant genes for glutathione peroxidase (GPx1) and Mn superoxide dismutase (Sod2) caused reduced energy production and neonatal lethal dilated cardiomyopathy, respectively, the later being ameliorated by treatment with MnSOD mimics. Partial Sod2 deficiency (+/-) resulted in mice with increased mitochondrial damage during aging, and treatment of C. elegans with catalytic antioxidant drugs can extend their life-span. Mice deficient in cytochrome-c died early in embryogenesis, but cells derived from these embryos had a complete deficiency in mitochondrial apoptosis. Mice lacking the proapoptotic Bax and Bak genes were not able to release cytochrome-c from the mitochondrion and were blocked in apoptosis. Mice lacking Apaf1, Cas9, and Cas3 did release mitochondrial cytochrome-c and were blocked in the downstream steps of apoptosis. These animal studies confirm that alterations in mitochondrial energy generation, ROS production, and apoptosis can all contribute to the pathophysiology of mitochondrial disease.