An accumulation of deletions of mitochondrial DNA (mtDNA), finally leading to mitochondrial dysfunction, has been found in many tissues during normal aging as well as in several age-related pathologies. Little is known about the molecular mechanisms involved in their generation and their clonal expansion over time. In particular, it is unclear why some tissues seem to preferentially accumulate these DNA alterations. One striking example are dopaminergic neurons in the Substantia nigra pars compacta of humans, where a drastic increase in deleted mtDNA molecules has been observed in Parkinsons disease and during normal aging, conditions under which these neurons degenerate. To test the hypothesis that dopamine metabolism is involved in their generation, we analyzed various mouse brain regions for three different mtDNA deletions, using qPCR and long range PCR, allowing the detection of both known and unknown deletions, respectively. Deletions were not found in 12 weeks old mice, but were detected at week 50 and increased with age. Deletions were most prominent in S. nigra, followed by striatum, cerebellum and cortex, as in humans. In addition, in the adrenal gland, the percentage of deleted vs. wild-type molecules was about 5fold higher than in S. nigra, supporting our hypothesis that a high turnover of catecholamines stimulates the generation and/or clonal expansion of mtDNA deletions. Neuroblastoma cell clones (SHSY5Y) stably overexpressing key enzymes of dopamine metabolism (tyrosine hydroxylase, monoamine oxidase, dopamine transporter) showed increased amounts of deleted mtDNA. We conclude that high catecholamine turnover is sufficient to to drive the generation of these deletions, leading to mitochondrial dysfunction which causes dopaminergic neuron death. Possible mechanisms leading to the selective death of a sub-population of vulnerable neurons will be discussed, based on single cell data.