Somatic mtDNA Mutation Burden Shapes Metabolic Plasticity in Leukemogenesis

The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorlycharacterized. To determine the impact of somatic mtDNA mutations on the process, we assessed theleukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A)with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesisin recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemiain those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygousand homozygous HPCs caused similar baseline impairments in mitochondrial function, onlyheterozygous HPCs responded to and supported altered metabolic demands associated with NMycoverexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenaseinhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growthof NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenasekinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity inleukemogenesis.