title: Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches.
abstract: Mitochondrial disorders are a group of highly invalidating human conditions for which effective treatment is currently unavailable and characterized by faulty energy supply due to defective oxidative phosphorylation (OXPHOS). Given the complexity of mitochondrial genetics and biochemistry, mitochondrial inherited diseases may present with a vast range of symptoms, organ involvement, severity, age of onset, and outcome. Despite the wide spectrum of clinical signs and biochemical underpinnings of this group of dis-orders, some common traits can be identified, based on both pathogenic mechanisms and potential therapeutic approaches. Here, we will review two peculiar mitochondrial disorders, ethylmalonic encephalopathy (EE) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), caused by mutations in the ETHE1 and TYMP nuclear genes, respectively. ETHE1 encodes for a mitochondrial enzyme involved in sulfide detoxification and TYMP for a cytosolic enzyme involved in the thymidine/deoxyuridine catabolic pathway. We will discuss these two clinical entities as a paradigm of mitochondrial diseases caused by the accumulation of compounds normally present in traces, which exerts a toxic and inhibitory effect on the OXPHOS system.
authors.affiliation: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Di Meo
authors.affiliation: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.affiliation: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy tiranti@istituto-besta.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tiranti
mesh_terms: D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D028361:Mitochondrial Diseases / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D024101:Mitochondrial Proteins / Q000235:genetics*; D039141:Muscular Dystrophy, Oculopharyngeal; D009154:Mutation; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics*; D009886:Ophthalmoplegia / Q000151:congenital; D011693:Purpura / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D013939:Thymidine Phosphorylase / Q000235:genetics*
chemical_list: C483228:ETHE1 protein, human; D024101:Mitochondrial Proteins; D029543:Nucleocytoplasmic Transport Proteins; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase
keywords: OXPHOS; mitochondrial diseases; sulfide catabolism; therapeutic approaches; thymidine/deoxyuridine catabolism