Abstract <p>The quantitative content of mitochondrial DNA (mtDNA) – a multicopy circular genome – is an important parameter relevant for function of mitochondrial oxidative phosphorylation (OxPhos) in cells, since mtDNA encodes 13 essential OxPhos proteins, 22 tRNAs, and 2 rRNAs. In contrast to the nuclear genome, where almost all lesions have to be repaired, the multicopy nature of mtDNA allows the degradation of severely damaged genomes. Therefore, cellular mtDNA maintenance and its copy number not only depend on replication speed and repair reactions. The speed of intramitochondrial mtDNA degradation performed by a POLGexo/MGME1/TWNK degradation complex and the breakdown rate of entire mitochondria (mitophagy) are also relevant for maintaining the required steady state levels of mtDNA. The present review discusses available information about the processes relevant for turnover of mitochondrial DNA, which dysbalance leads to mtDNA maintenance disorders. This group of mitochondrial diseases is defined by pathological decrease of cellular mtDNA copy number and can be separated in diseases related to decreased mtDNA synthesis rates (due to direct replication defects or mitochondrial nucleotide pool dysbalance) or diseases related to increased breakdown of entire mitochondria (due to elevated mitophagy rates).</p>