Abstract

Since the end of nineties numerous mitochondrial diseases have been found to be related to mutations in nuclear genes encoding mitochondrial carriers, a family of proteins that shuttle a variety of metabolites across the mitochondrial membrane. To date eleven disorders are known to be caused by defects of mitochondrial carriers. Mutations of mitochondrial carrier genes are responsible for carnitine/acylcarnitine carrier deficiency, ornithine carrier deficiency (HHH syndrome), aspartate/glutamate isoform 1 deficiency (global cerebral hypomyelination), aspartate/glutamate isoform 2 deficiency (CTLN2 and NICCD), amish microcephaly, neonatal myoclonic epilepsy, congenital sideroblastic anemia, PiC deficiency, ADP/ATP carrier isoform 1 deficiency and involved in neuropathy and bilateral striatal necrosis and adPEO (autosomal dominant progressive external ophthalmoplegia). We propose un updated overview of these diseases. We shall also discuss the role of missense mutations in impairing mitochondrial carrier function and the consequent severe damage to the mitochondrial matrix supply with substrates destined to specific metabolic pathways. Despite the substantial progress that has been made in our understanding of the molecular bases of mitochondrial carrier associated diseases, specific pharmacological therapies are not yet available. Current therapies are symptomatic and usually based on specific dietary measures. New therapeutic approaches are under investigation for some of these diseases. For further reading Palmieri F. (2008) Diseases caused by defects of mitochondrial carriers: a review. Biochim Biophys Acta; 1777:564-78. Palmieri F, Pierri CL (2010) Structure and function of mitochondrial carriers - Role of the transmembrane helix P and G residues in the gating and transport mechanism. FEBS Lett. 584:1931-9. Tessa A, Fiermonte G, Dionisi-Vici C, Paradies E, Baumgartner MR, Chien YH,Loguercio C, de Baulny HO, Nassogne MC, Schiff M, Deodato F, Parenti G, Rutledge SL, Vilaseca MA, Melone MA, Scarano G, Aldamiz-Echevarría L, Besley G, Walter J, Martinez-Hernandez E, Hernandez JM, Pierri CL, Palmieri F, Santorelli FM. (2009) Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Human Mutation; 30:741-8. Wibom R, Lasorsa FM, Töhönen V, Barbaro M, Sterky FH, Kucinski T, Naess K, Jonsson M, Pierri CL, Palmieri F, Wedell A. (2009) AGC1 deficiency associated with global cerebral hypomyelination. N Engl J Med.; 361:489-95. Iacobazzi V, Convertini P, Infantino V, Scarcia P, Todisco S, Palmieri F. (2009) Statins, fibrates and retinoic acid upregulate mitochondrial acylcarinitine carrier gene expression. Biochem Biophys Res Commun.; 388:643-7.

Autore Pugliese

• Pierri Ciro Leonardo

Tutti gli autori

• PIERRI C.L.

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Anno di pubblicazione

2011

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