title: Impaired transport of nucleotides in a mitochondrial carrier explains severe human genetic diseases.
abstract: The mitochondrial ADP/ATP carrier (AAC) is a prominent actor in the energetic regulation of the cell, importing ADP into the mitochondria and exporting ATP toward the cytoplasm. Severe genetic diseases have been ascribed to specific mutations in this membrane protein. How minute, well-localized modifications of the transporter impact the function of the mitochondria remains, however, largely unclear. Here, for the first time, the relationship between all documented pathological mutations of the AAC and its transport properties is established. Activity measurements combined synergistically with molecular-dynamics simulations demonstrate how all documented pathological mutations alter the binding affinity and the translocation kinetics of the nucleotides. Throwing a bridge between the pathologies and their molecular origins, these results reveal two distinct mechanisms responsible for AAC-related genetic disorders, wherein the mutations either modulate the association of the nucleotides to the carrier by modifying its electrostatic signature or reduce its conformational plasticity.
authors.affiliation: Université Grenoble, IBS, Institut de Biologie Structurale, Grenoble, France. stephanie.ravaud@ibs.fr
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ravaud
authors.forename: Axel
authors.initials: A
authors.lastname: Bidon-Chanal
authors.forename: Iulia
authors.initials: I
authors.lastname: Blesneac
authors.forename: Paul
authors.initials: P
authors.lastname: Machillot
authors.forename: Céline
authors.initials: C
authors.lastname: Juillan-Binard
authors.forename: François
authors.initials: F
authors.lastname: Dehez
authors.forename: Chris
authors.initials: C
authors.lastname: Chipot
authors.forename: Eva
authors.initials: E
authors.lastname: Pebay-Peyroula
mesh_terms: D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009711:Nucleotides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation / Q000502:physiology; D017433:Protein Structure, Secondary; D021381:Protein Transport / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: D009711:Nucleotides; D000226:Mitochondrial ADP, ATP Translocases