The oxidative phosphorylation system (OXPHOS) in the mitochondrial inner membrane is crucial for producing ATP from food. OXPHOS relies on mitochondrial DNA (mtDNA) and nuclear genes, making it vulnerable to mutations that can lead to mitochondrial and age-related diseases. Mammalian mtDNA is maternally transmitted without recombination, which should theoretically cause a mutational meltdown over generations. However, mechanisms like the bottleneck effect and purifying selection help prevent this. The pathophysiology of mitochondrial dysfunction remains poorly understood, with heteroplasmy (coexistence of mutated and wildtype mtDNA) complicating the picture. Recent advances, such as base editing, now allow the creation of mouse models with specific mtDNA mutations, aiding in the study of these issues. Somatic mtDNA mutations, present in all human tissues, accumulate over time and contribute to disease. The mtDNA mutator mouse model, with a D257A mutation in POLG, shows accelerated aging features, highlighting the impact of mtDNA mutations on aging. Using new technology to generate mice with mtDNA mutations, we aim to study the pathophysiology and transmission mechanisms of inherited and somatic mtDNA mutations.