title: Porphyrin accumulation in mitochondria is mediated by 2-oxoglutarate carrier.
abstract: Heme (Fe-protoporphyrin IX), an endogenous porphyrin derivative, is an essential molecule in living aerobic organisms and plays a role in a variety of physiological processes such as oxygen transport, respiration, and signal transduction. For the biosynthesis of heme or the mitochondrial heme proteins, heme or its biosynthetic precursor porphyrin must be transported into mitochondria from cytosol. The mechanism of porphyrin accumulation in the mitochondrial inner membrane is unclear. In the present study, we analyzed the mechanism of mitochondrial translocation of porphyrin derivatives. We showed that palladium meso-tetra(4-carboxyphenyl)porphyrin (PdTCPP), a phosphorescent porphyrin derivative, accumulated in the mitochondria of several cell lines. Using affinity latex beads, we showed that 2-oxoglutarate carrier (OGC), the mitochondrial transporter of 2-oxoglutarate, bound to PdTCPP, and in vitro PdTCPP inhibited 2-oxoglutarate uptake into mitochondria in a competitive manner (Ki = 15 microM). Interestingly, all types of porphyrin derivatives examined in this study competitively inhibited 2-oxoglutarate uptake into mitochondria, including protoporphyrin IX, coproporphyrin III, and hemin. Furthermore, mitochondrial accumulation of porphyrins was inhibited by 2-oxoglutarate or OGC inhibitor. These results suggested that porphyrin accumulation in mitochondria is mediated by OGC and that porphyrins are able to competitively inhibit 2-oxoglutarate uptake into mitochondria. This is the first report of a putative mechanism for accumulation of porphyrins in the mitochondrial inner membrane.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
authors.forename: Masashi
authors.initials: M
authors.lastname: Ohmori
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinouchi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Tsuboi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirao
authors.forename: Motoki
authors.initials: M
authors.lastname: Azuma
authors.forename: Hajime
authors.initials: H
authors.lastname: Watanabe
authors.forename: Ichiro
authors.initials: I
authors.lastname: Okura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006367:HeLa Cells; D006418:Heme / Q000737:chemistry; D006427:Hemin / Q000737:chemistry; D006801:Humans; D007656:Ketoglutaric Acids / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013386:Succinates / Q000737:chemistry
chemical_list: D007656:Ketoglutaric Acids; D011166:Porphyrins; D013386:Succinates; D006418:Heme; C017625:2-phenylsuccinate; D006427:Hemin