Mutant mitochondrial DNA sequence (mutant mtDNA)

Mitochondrial DNA (mtDNA) is a small, circular genome located within the mitochondria that encodes 13 essential subunits of the respiratory chain, along with necessary ribosomal and transfer RNAs. Mutations in these sequences, which can be inherited maternally or acquired somatically, lead to mitochondrial dysfunction and a variety of multi-systemic disorders known as mitochondrial diseases (Gorman et al., 2016, Nature Reviews Disease Primers). A unique feature of mtDNA is heteroplasmy, where mutant and wild-type genomes coexist within a single cell; disease symptoms typically manifest only when the proportion of mutant mtDNA exceeds a critical threshold (Stewart & Chinnery, 2015, Nature Reviews Genetics). Therapeutic strategies targeting mutant mtDNA sequences aim to selectively eliminate or correct these pathogenic variants to shift heteroplasmy levels back toward the wild-type, thereby restoring cellular energy production. Current experimental approaches include the use of mitochondria-targeted nucleases, such as Zinc Finger Nucleases (mtZFNs) and Transcription Activator-Like Effector Nucleases (MitoTALENs), which induce targeted degradation of mutant genomes (Gammage et al., 2018, Nature Medicine). More recently, base editing technologies like DdCBE have been developed to enable precise nucleotide corrections within the mitochondria without requiring double-strand breaks (Mok et al., 2020, Nature). Despite their promise, these therapies face significant hurdles, including the need for efficient delivery across the double mitochondrial membrane and the prevention of off-target effects on the nuclear or wild-type mitochondrial genomes (Silva-Pinheiro & Minczuk, 2022, Trends in Genetics).

Other names

Pathogenic mtDNA variantsMutated mitochondrial genomeHeteroplasmic mtDNA mutationsmtDNA mutations

Heteroplasmy shifting via selective degradation of mutant mtDNA; Site-specific base editing.