Systematic zebrafish atlas of mitochondrial genome loss-of-function alleles published in preprint

A preprint on bioRxiv describes the construction of Z-Terminator, a systematic in vivo atlas of loss-of-function (LOF) alleles for all 13 protein-coding genes of the mitochondrial genome in zebrafish (Danio rerio). The work addresses a significant gap in mitochondrial disease research: despite pathogenic variants in mtDNA-encoded genes being known to underlie a diverse and clinically heterogeneous group of disorders, most of these genes have lacked defined in vivo LOF models.

The team used mitochondrial TALE base editors — a class of programmable base-editing tools adapted for the mitochondrial genome — to introduce premature termination codon (PTC) alleles via C-to-T transitions across components of the oxidative phosphorylation (OXPHOS) system: Complexes I, III, IV, and V. Zebrafish larvae harbouring PTC alleles are reported to display bioenergetic phenotypes consistent with OXPHOS dysfunction.

The atlas is of broad utility for researchers studying mitochondrial disease mechanisms, genotype–phenotype relationships in mitochondrial disorders, and the in vivo consequences of heteroplasmy. The zebrafish system offers advantages in terms of transparency, reproductive rate, and tractability for phenotypic readouts. Mitochondrial base editing in vivo remains technically demanding and the preprint has not yet undergone peer review.

For researchers in mitochondrial medicine, clinical genetics of mitochondrial disorders, and functional genomics, Z-Terminator represents a resource likely to support downstream mechanistic studies. Educators teaching mitochondrial genetics and gene-editing methodologies may find the study design illustrative of emerging base-editor applications beyond the nuclear genome.