title: BNIP3 and NIX mediate Mieap-induced accumulation of lysosomal proteins within mitochondria.
abstract: Mieap, a p53-inducible protein, controls mitochondrial quality by repairing unhealthy mitochondria. During repair, Mieap induces the accumulation of intramitochondrial lysosomal proteins (designated MALM for Mieap-induced accumulation of lysosome-like organelles within mitochondria) by interacting with NIX, leading to the elimination of oxidized mitochondrial proteins. Here, we report that an additional mitochondrial outer membrane protein, BNIP3, is also involved in MALM. BNIP3 interacts with Mieap in a reactive oxygen species (ROS)-dependent manner via the BH3 domain of BNIP3 and the coiled-coil domains of Mieap. The knockdown of endogenous BNIP3 expression severely inhibited MALM. Although the overexpression of either BNIP3 or NIX did not cause a remarkable change in the mitochondrial membrane potential (MMP), the co-expression of all three exogenous proteins, Mieap, BNIP3 and NIX, caused a dramatic reduction in MMP, implying that the physical interaction of Mieap, BNIP3 and NIX at the mitochondrial outer membrane may regulate the opening of a pore in the mitochondrial double membrane. This effect was not related to cell death. These results suggest that two mitochondrial outer membrane proteins, BNIP3 and NIX, mediate MALM in order to maintain mitochondrial integrity. The physical interaction of Mieap, BNIP3 and NIX at the mitochondrial outer membrane may play a critical role in the translocation of lysosomal proteins from the cytoplasm to the mitochondrial matrix.
authors.affiliation: Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kitamura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Shinogi
authors.forename: Masaki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Olga
authors.initials: O
authors.lastname: Goda
authors.forename: Ryuya
authors.initials: R
authors.lastname: Murai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kamino
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Arakawa
mesh_terms: D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D015388:Organelles / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; C474007:Bax protein (53-86); D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D011506:Proteins; D011518:Proto-Oncogene Proteins; C558496:SPATA18 protein, human; D025521:Tumor Suppressor Proteins; C018589:lysosomal proteins