With life expectancies increasing around the world, neurodegenerative disorders and other late-onset inflictions represent an enormous disease burden. A cellular hallmark of these diseases is a loss of mitochondrial function. Mitochondria are the organelles within our cells that convert the calories we eat into the primary energy substrate of the cell, ATP. These organelles harbour their own genome (mtDNA), which is essential for mitochondrial function but prone to mutation and molecular lesion. A gradual build of mtDNA damage during time has been proposed to contribute to the progressive nature of late-onset diseases. Moreover, mtDNA mutations are transmissible to the next generation and can cause a range of devastating metabolic disorders called mitochondrial diseases. Using novel approaches to purify cell-specific mitochondria across large populations of animals, we have discovered that mutations in mtDNA follow a stereotyped pattern of distribution in different tissue types. Our results suggest that certain cells are prone to propagating mitochondrial mutations more than others, which may help to explain the mosaic pattern of tissue and organ dysfunction in patients carrying mtDNA mutations. We have identified that mitochondrial autophagy (mitophagy) driven by the PINK1-parkin axis determines the stereotyped patterns of mosaicism within somatic tissues and organs. Interestingly, we also discovered that germ cells harboured the highest level of mtDNA mutations – a surprising finding considering that these mitochondria are transmitted to the next generation. I will present our latest findings on this phenomenon as well as discuss the results of a genome-wide genetic screen designed to discover molecules that can counteract the effects of mtDNA damage, which inevitably accumulates over our lifetimes.