Numerous mitochondrial DNA (mtDNA) variants are associated with cancers, yet the causal link remains inconclusive. Using DddA-derived cytosine base editors, we induced truncating mutations in in HEK293 cells, establishing heteroplasmy, the coexistence of mutant and wild-type mtDNA. This study aimed to investigate the full molecular etiology following these deleterious mtDNA mutations, particularly in oncogenesis. We found that low to moderate heteroplasmic levels of the mutants were sufficient to impair mitochondrial functions and alter cellular redox status. Cellular adaptation to elevated ROS (Reactive Oxygen Species), energy crisis, and altered redox status was observed across varying heteroplasmy levels. Increased oncogenic potential was confirmed through oncogenesis and xenograft assays. Transcriptomic analysis revealed upregulated migration, invasion, and genome instability pathways, and downregulated ROS scavenging pathways. Our results demonstrate that mutations drive cancer progression by increasing cellular ROS and genome instability, and by altering the redox balance and epigenetic landscapes.