Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome
Pathogenic variants in the 13 protein-coding genes of the mitochondrial genome underlie clinically and biochemically heterogeneous disorders. Most mtDNA-encoded genes lack defined loss-of-function (LOF) models in vivo. To address this gap, we have generated Z-Terminator, a systematic in vivo atlas of loss-of-function alleles covering all the mtDNA-encoded OXPHOS subunits in zebrafish (Danio…
A research team has developed a comprehensive in vivo resource to study the impact of loss-of-function alleles in the mitochondrial proteome of zebrafish. The study, titled "Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome," focuses on uncovering the cellular basis of sensorineural hearing loss linked to mitochondrial DNA mutations.
The researchers employed a technique called mitochondrial TALE base editors to introduce premature termination codon (PTC) alleles into the mitochondrial genome of zebrafish (Danio rerio). These PTC alleles were created across all four mitochondrial complexes (I, III, IV, and V) responsible for oxidative phosphorylation.
The resulting Z-Terminator resource allows for the study of loss-of-function alleles in a living vertebrate. The researchers observed that these engineered mtDNA LOF alleles directly impair hair cell function in proportion to heteroplasmy levels. They also investigated the germline transmission and tissue-specific heteroplasmy of these alleles, finding that some variants were passed on to the F1 generation and displayed varying mutant loads across different organs.
This systematic approach establishes Z-Terminator as a valuable platform for investigating the role of mitochondrial protein-coding genes in cellular dysfunction and for understanding the pathophysiology of mitochondrial disorders.
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