In most eukaryotic cells, mitochondrial DNA (mtDNA) is uniparentally transmitted and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA; all copies are therefore near-identical, or homoplasmic. Heteroplasmy, the presence of more than one mtDNA variant in the same cytoplasm, can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases or improving fertility that can generate heteroplasmy between divergent non-pathological mtDNAs (DNPH). We performed the characterization of engineered heteroplasmic mice throughout their lifespan through transcriptomic, metabolomic, biochemical, physiological and phenotyping studies. Using in vivo imaging techniques for non-invasive assessment of cardiac and pulmonary energy metabolism we demostrate that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death.

Short Bio:
Ana Victoria completed her PhD at the Spanish National Centre for Cardiovascular Research in Madrid (CNIC), with particular focus on mitochondrial transfer from mothers to their offspring and the mechanisms that regulate mitochondrial DNA segregation in mitochondrial diseases. Biotechnologist and biochemist with a keen interest in immunology and mitochondrial quality control, she contributed during her first postdoctoral position to the elucidation of how resident cardiac macrophages contribute to global tissue homeostasis by active local elimination of cardiomyocyte-derived mitochondria. In 2020, she moved into the group of Prof. Vincenzo Cerundolo at Weatherall Institute of Molecular Medicine (University of Oxford) with a Fundación Alfonso Martin Escudero Postdoctoral Fellowship to study the role and identification of immunogenic neo-epitopes derived from mitochondrial-derived peptides that are expressed during the tumoral metabolic switch. After securing an EMBO Long Term Postdoctoral Fellowship, Ana Victoria joined in 2021 the lab of Prof. Katja Simon at the Kennedy Institute of Rheumatology (University of Oxford) to pursue her interest in immunometabolism. She will study how the mitochondrial genetics and different mitochondrial metabolic signatures impacts in the selective removal of the organelle during T cell reprogramming and senescence.