title: Mitochondrial translocation of APE1 relies on the MIA pathway.
abstract: APE1 is a multifunctional protein with a fundamental role in repairing nuclear and mitochondrial DNA lesions caused by oxidative and alkylating agents. Unfortunately, comprehensions of the mechanisms regulating APE1 intracellular trafficking are still fragmentary and contrasting. Recent data demonstrate that APE1 interacts with the mitochondrial import and assembly protein Mia40 suggesting the involvement of a redox-assisted mechanism, dependent on the disulfide transfer system, to be responsible of APE1 trafficking into the mitochondria. The MIA pathway is an import machinery that uses a redox system for cysteine enriched proteins to drive them in this compartment. It is composed by two main proteins: Mia40 is the oxidoreductase that catalyzes the formation of the disulfide bonds in the substrate, while ALR reoxidizes Mia40 after the import. In this study, we demonstrated that: (i) APE1 and Mia40 interact through disulfide bond formation; and (ii) Mia40 expression levels directly affect APE1's mitochondrial translocation and, consequently, play a role in the maintenance of mitochondrial DNA integrity. In summary, our data strongly support the hypothesis of a redox-assisted mechanism, dependent on Mia40, in controlling APE1 translocation into the mitochondrial inner membrane space and thus highlight the role of this protein transport pathway in the maintenance of mitochondrial DNA stability and cell survival.
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine 33100, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Barchiesi
authors.affiliation: International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Wasilewski
authors.affiliation: International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chacinska
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine 33100, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine 33100, Italy carlo.vascotto@uniud.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Vascotto
mesh_terms: D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009154:Mutation; D055550:Protein Stability; D021381:Protein Transport
chemical_list: C507282:CHCHD4 protein, human; D004272:DNA, Mitochondrial; D004220:Disulfides; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D003545:Cysteine