title: Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia.
abstract: Heme is an essential molecule in many biological processes, such as transport and storage of oxygen and electron transfer as well as a structural component of hemoproteins. Defects of heme biosynthesis in developing erythroblasts have profound medical implications, as represented by sideroblastic anemia. The synthesis of heme requires the uptake of glycine into the mitochondrial matrix where glycine is condensed with succinyl coenzyme A to yield δ-aminolevulinic acid. Herein we describe the biochemical and molecular characterization of yeast Hem25p and human SLC25A38, providing evidence that they are mitochondrial carriers for glycine. In particular, the hem25Δ mutant manifests a defect in the biosynthesis of δ-aminolevulinic acid and displays reduced levels of downstream heme and mitochondrial cytochromes. The observed defects are rescued by complementation with yeast HEM25 or human SLC25A38 genes. Our results identify new proteins in the heme biosynthetic pathway and demonstrate that Hem25p and its human orthologue SLC25A38 are the main mitochondrial glycine transporters required for heme synthesis, providing definitive evidence of their previously proposed glycine transport function. Furthermore, our work may suggest new therapeutic approaches for the treatment of congenital sideroblastic anemia.
authors.affiliation: From the Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Lunetti
authors.affiliation: From the Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Damiano
authors.affiliation: Laboratory of Analytical and Isotopic Mass Spectrometry, Department of Cultural Heritage, University of Salento, 73100 Lecce, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Benedetto
authors.affiliation: From the Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Siculella
authors.affiliation: Laboratory of Analytical and Isotopic Mass Spectrometry, Department of Cultural Heritage, University of Salento, 73100 Lecce, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pennetta
authors.affiliation: Department of Pharmacy, Health, and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy.
authors.forename: Luigina
authors.initials: L
authors.lastname: Muto
authors.affiliation: Consiglio Nazionale delle Ricerche, Institute of Biomembranes and Bioenergetics, 70125 Bari, Italy, and.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Paradies
authors.affiliation: Department of Biosciences, Biotechnology, and Pharmacological Sciences, University of Bari, 70125 Bari, Italy.
authors.forename: Carlo Marya Thomas
authors.initials: CM
authors.lastname: Marobbio
authors.affiliation: Department of Pharmacy, Health, and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Dolce
authors.affiliation: From the Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
authors.forename: Loredana
authors.identifier: 0000-0002-9058-7743
authors.initials: L
authors.lastname: Capobianco
mesh_terms: D000740:Anemia / Q000235:genetics / Q000378:metabolism*; D005816:Genetic Complementation Test; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; C553226:Slc25a38 protein, human; D006418:Heme; D005998:Glycine
keywords: HEM25; SLC25A38; amino acid transport; heme; heme synthesis; mitochondrial glycine carrier; mitochondrial respiratory chain complex; mitochondrial transport; sideroblastic anemia; yeast metabolism