The patients were three siblings born of consanguineous parents. They all had congenital cataracts and various degrees of psychomotor delay, hypotonia, hearing loss, bilateral or unilateral ptosis, sensorineural hearing loss, and lactic acidosis. At age 17 years, the older sibling needed tutorial assistance at school and was hyporeflexic. His brain MRI only showed thinning of the corpus Inhibitors,research,lifescience,medical callosum. Muscle histochemistry showed

scattered COX-negative, SDH-hyperintense fibers and ultrastructural studies revealed vacuolated mitochondria with thickened cristae. Biochemical analysis showed partial decrease of COX (30%-50% residual activity) and less severe reduction of complexes I and II. Homozygosity mapping led to the

identification of a missense mutation in the gene (GFER) whose product belongs to the ERV1/ALR protein family. Inhibitors,research,lifescience,medical Yeast Erv1p (and presumably its human counterpart GFER, a sulfhydryl oxidase) oxidizes the disulfide carrier protein Mia40, which, in turn, transfers a disulfide to newly synthesized proteins in the mitochondrial IMS. The reoxidaton of Erv1p is Inhibitors,research,lifescience,medical mediated by cytochrome c and COX, thus linking the DRS to the mitochondrial respiratory chain. Comi and coworkers showed that the mutant GFER is unstable and its concentration decreases in mitochondria, thus probably inhibiting the import of DRS substrates, including COX17, TIMM13, and COX6B1 (25). It is noteworthy that a mutation in COX6B1 has been the first example of a “direct hit” in complex IV deficiency (26). It is also noteworthy that defects of the DRS are yet another cause of multiple mtDNA deletions, Inhibitors,research,lifescience,medical which were documented in muscle from one of the patients with mutant GFER (25). As I mentioned

in a recent historical review (21) for now at least, the last frontier of research in mitochondrial disorders seems to be the defects of mitochondrial translation. Within the past four years, often through homozygosity mapping, defects have been discovered in genes controlling factors at all levels of the complex translation Inhibitors,research,lifescience,medical apparatus, from rRNA base modification, such as MRPS16 (27) to general translation, such Megestrol Acetate as EFG1 (now called GFM1) (28-31) to tRNA processing and base modification, such as PUS1 (32) to tRNA synthetase (33, 34). This subject has been recently and lucidly reviewed by Smits et al. (35). Therapy This is very much an area of work in progress, but there are three developments that are worth discussing briefly: stem cell therapy in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); boosting mitochondrial biogenesis as a therapeutic strategy; and pronuclear transfer as a preventive measure to mtDNA-related disorders. MNGIE is an BMS-754807 clinical trial autosomal recessive multisystemic disease characterized clinically by progressive external ophthalmoplegia (PEO), ptosis, gastrointestinal dysmotility, extreme cachexia, peripheral neuropathy, leukoencephalopathy, and death in early or mid-adulthood (36).