Journal
BIOMOLECULES
Volume 10, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/biom10040655
Keywords
disease; error of metabolism; mitochondrial carrier; mitochondrial carrier disease; mitochondrial disease; mitochondrial transporter; membrane transport; mutation; SLC25
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Funding
- Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR)
- Centre of Excellence Genomics: genes involved in pathopysiological processes in the biomedical and agricultural fields (CEGBA)
- Comitato Telethon Fondazione Onlus [GGP11139]
- Italian Human ProteomeNet
- PRIN 2017 [2017PAB8EM_004]
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In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. Agroup of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.
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