A magic bullet to specifically eliminate mutated mitochondrial genomes from patients' cells

Abstract

When mitochondrial diseases result from mutations found in the mitochondrial DNA, engineered mitochondrial-targeted nucleases such as mitochondrial-targeted zinc finger nucleases are shown to specifically eliminate the mutated molecules, leaving the wild-type mitochondrial DNA intact to replicate and restore normal copy number. In this issue, Gammage and colleagues successfully apply this improved technology on patients' cells with two types of genetic alterations responsible for neuropathy ataxia and retinitis pigmentosa (NARP) syndrome and Kearns Sayre syndrome and progressive external ophthalmoplegia (PEO).

Figure 1

Mitochondrial-targeted nucleases such as mtZFN (Gammage et al, 2014) or mitoTALEN (Bacman et al, 2013) can specifically eliminate mutated mtDNA molecules, leaving the wild-type mtDNA intact. After a double-strand break, most molecules are rapidly degraded. The residual mtDNA is stimulated to replicate and restore the normal mtDNA copy number. The final result is a cell with higher levels of wild-type mtDNA and an improved biochemical phenotype, as shown by Gammage and colleagues in this issue (Gammage et al, 2014).