If it is true that from the beginning of mitochondrial genetics

there has been a lot of handwaving about nuclear factors modulating the phenotypic expression of mtDNA mutations, now this has become a present and immediate question demanding that we identify the putative “nuclear modifiers” and understand their mechanism of action. In the long course of their migration out of Africa, which started about 150,000 year ago, our ancestors accumulated harmless mtDNA changes (polymorphisms) Inhibitors,research,lifescience,medical that differed among different populations and still define ethnic groups (19). It was proposed that these ancient variations are not only harmless but, in fact, adaptive, thus facilitating the settlement of different groups in favorable ecological niches (20). Inhibitors,research,lifescience,medical Thus, for example, a mtDNA variation conducive to loose coupling of oxidative phosphorylation (OXPHOS) would enhance the dissipation of energy as heat and be advantageous to people living in frigid climates. Although their effect on OXPHOS would be small, haplogroup-defining mutations might behave as susceptibility factors in multifactorial diseases, in Inhibitors,research,lifescience,medical the context of particular environmental or nuclear factors. Such small effect on OXPHOS has been documented by “homogenizing” environmental and nuclear backgrounds with

the use of cybrid cell lines, that is, immortalized human cell lines emptied of their own mtDNA and repopulated with haplotype-specific mitochondria (19). Inhibitors,research,lifescience,medical Mendelian mitochondrial disorders With the term “indirect hits” we refer to mutations in nuclear genes that do not affect respiratory chain subunits directly, but

alter proteins needed for the assembly and maintenance of respiratory chain complexes. Numerous such indirect hits Inhibitors,research,lifescience,medical have been associated with defects in all five complexes of the respiratory chain (21), but Valeria Tiranti and Massimo Zeviani in Milan, Italy, have discovered a novel type of indirect hit, where the second whammy is toxic instead of structural. First, using integrative genomics, they found that ethylmalonic encephalomyopathy (EE), a devastating early-onset disorder with encephalopathy, microangiopathy, chronic diarrhea, and massively increased levels of ethylmalonic acid Isotretinoin and short-chain acylcarnitines in body fluids, was due to mutations in the ETHE1 gene (22). They then documented that ETHE1 is a mitochondrial matrix thioesterase (23) and created an Ethe1-null mouse, which led them to discover that thiosulfate and sulfide accumulate excessively both in the animal model and in affected children due to the lack of sulfur dioxygenase activity (24). As sulfide is a Kinase Inhibitor Library ic50 powerful COX inhibitor, what they described was an indirect hit of a toxic kind and likely the prototype of other similar pathogenic mechanisms.