Human mitochondria harbor an essential, high copy number, 16,569 base pair, 
circular DNA genome that encodes 13 gene products required for electron 
transport and oxidative phosphorylation. Mutation of this genome can compromise 
cellular respiration, ultimately resulting in a variety of progressive metabolic 
diseases collectively known as 'mitochondrial diseases'. Mutagenesis of mtDNA 
and the persistence of mtDNA mutations in cells and tissues is a complex topic, 
involving the interplay of DNA replication, DNA damage and repair, purifying 
selection, organelle dynamics, mitophagy, and aging. We briefly review these 
general elements that affect maintenance of mtDNA, and we focus on nuclear genes 
encoding the mtDNA replication machinery that can perturb the genetic integrity 
of the mitochondrial genome.