Typically, these findings have been shown in patients harbouring the common m.3243A>G mutation associated with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) where stroke-like episodes are particularly frequent (Betts et al., 2006).
To test the generality of the approach, we designed mitoTALENs to target two relatively common pathogenic mtDNA point mutations associated with mitochondrial diseases: the m.8344A>G tRNALys gene mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) and the m.13513G>A ND5 mutation associated with MELAS/Leigh syndrome.
Out of these, 12 are novel mutations and remaining 15 are already known mutations associated with mitochondrial diseases (Table 3).
The vast majority were located in coding regions; however, mutations associated with mitochondrial disease have not been reported at any of these positions (www.MITOMAP.org).
Recent studies have shown that majority of mutations associated with mitochondrial diseases remain unidentified occurring either in mtDNA or nuclear DNA [11].
However, both Pol ζ and Rev1 are responsible for the majority of spontaneous and UV-induced frameshift mutations associated with mitochondrial microsatellite sequences and UV-induced petite formation (Kalifa and Sia 2007).
Charcot Marie Tooth disease-linked mutations interfere with mitochondrial transport by affecting motor protein complexes and the integrity of the cytoskeleton (Niemann et al., 2006; Baloh, 2008; Vital and Vital, 2012).
In conclusion, we have confirmed that the G2019S LRRK2 mutation is associated with mitochondrial uncoupling leading to a decreased mitochondrial membrane potential and decreased ADP phosphorylation.
These changes were not limited to those harbouring the m.3243A>G mutation frequently associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, but were documented in patients harbouring m.8344A>G and autosomal recessive polymerase (DNA directed), gamma (POLG) mutations.
However, it should be borne in mind that mtDNA mutations need not damage an organism: indeed, mutations in genes with mitochondrial function can increase lifespan [ 22].
