IDENTIFICAZIONE DI UNA NUOVA CAUSA GENETICA IN UN CASO FAMILIARE DI ENCEFALOMIOPATIA MITOCONDRIALE E DEFICIT DI CITOCROMO C OSSIDASI.

Using a linkage whole-genome SNP genotyping, we identified a missense mutation within the GFER gene as the cause of an infantile progressive mitochondrial myopathy. The human GFER (growth factor ERV1 homolog), also called ALR (augmenter of liver regeneration), belongs to the ERV1/ALR sulfhydryl oxidase family, which requires flavin adenine dinucleotide (FAD) as a cofactor. The physiological role of Erv1 has been elucidated in S. cerevisiae. ERV1 is an essential gene whose product is localized to the mitochondrial IMS. Together with Mia40, it participates in the DRS that drives the import of small IMS proteins to their final localization. Briefly, the DRS consists of two essential components: the sulfhydryl oxidase Erv1 (homolog to human GFER) and the redox-regulated import receptor Mia40. The DRS drives the import of cysteine-rich proteins into the IMS by an oxidative folding mechanism. Erv1p is reoxidized within this system, transferring its electrons onto molecular oxygen via interaction with cytochrome c and Cytochrome c Oxidase (COX), thereby linking the DRS to respiratory chain activity. Proteins belonging to the class of IMS, substrates of the DRS, are only partially identified. These include: a) small Tim proteins, chaperones involved in transport from the outer to the inner mitochondrial membrane; b) proteins involved in COX assembly; c) protein involved in protection from superoxide radicals generated by cellular respiration. The consequence of the mutation at the muscle and fibroblast levels are: 1) reduction of multiple mitochondrial respiratory chain complexes activity (predominantly Complex IV), which was restored by overexpression of the wild-type protein; 2) impaired import of human cysteine-rich proteins, known to be imported through the DRS in yeast, into mitochondria; 3) abnormal mitochondrial ultrastructural morphology, with enlargement of the IMS; 4) defective mtDNA maintenance, with accelerated time-dependent accumulation of multiple mtDNA deletions. Moreover, the Saccharomyces cerevisiae erv1R182H mutant strain reproduced the Complex IV activity defect and showed genetic instability of mtDNA and mitochondrial morphological defects. The aforementioned findings shed light on novel mechanisms of mitochondrial biogenesis and mtDNA maintenance, establish the role of ERV1 homologue in the human DRS, and promote the understanding of pathogenesis of a novel form of mitochondrial-related disease.