Project Grant R35GM166237

The National Institute of General Medical Sciences awarded University of Texas at Austin $434,480 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to elucidate the mechanisms of mitochondrial DNA heteroplasmy quality control.

The project investigates how mitochondrial genomes maintain fidelity when both wild-type and mutant mtDNA coexist (heteroplasmy), and how tissue-specific thresholds govern mitochondrial function. The research leverages zebrafish (Danio rerio) models with mitochondrial-targeted base editing to recapitulate human mtDNA dysfunction and track variants in vivo. The zebrafish mitochondrial genome shares high sequence similarity, identical gene complement, and complete synteny with the human mitochondrial genome, providing a vertebrate-relevant platform. Preliminary work revealed that germline segregation of mtDNA varies by genetic loci, challenging universal quality control models. The project tests the hypothesis that distinct molecular pathways regulate mtDNA heteroplasmy in germline versus somatic tissues through mito-nuclear crosstalk. Research objectives include identifying molecular machinery that distinguishes single nucleotide variations in mtDNA sequences using reverse genetic screening to map nuclear genes involved in quality control.

Performance occurs at Austin, Texas. The award period runs through April 30, 2031. University of Texas System is the parent organization.