HARS1 and Charcot-Marie-Tooth disease: While mitochondrial dysfunction has not been explicitly ruled out as an activator of the ISR in mouse models of CMT2D, the fact that TyrRS (and all of the other known CMT-associated synthetases, AlaRS, HisRS, MetRS, and TrpRS) is cytosolic and not mitochondrial, yet CMT-associated YARS mutations in mice and humans cause a similar phenotype, argues against mitochondrial involvement as the primary disease mechanism.