title: The non-glycosylated isoform of MIC26 is a constituent of the mammalian MICOS complex and promotes formation of crista junctions.
abstract: Mitochondrial membrane architecture is important for organelle function. Alterations thereof are linked to a number of human disorders including diabetes and cardiomyopathy. The MICOS complex was recently reported to be a central player determining cristae structure and formation of crista junctions. Here we investigated the functional role of MIC26, a lipoprotein formerly termed APOO. Its levels are increased in diabetic heart tissue and in blood plasma of patients suffering from acute coronary syndrome. We demonstrate that human MIC26 exists in three distinct forms: (1) a glycosylated and secreted 55kDa protein, (2) an ER/Golgi-resident form thereof, and (3) a non-glycosylated 22kDa mitochondrial protein. The latter isoform spans the mitochondrial inner membrane and physically interacts with several MICOS complex subunits such as MIC60, MIC27, and MIC10. We further demonstrate that MIC26 and MIC27, a homologous protein formerly termed APOOL, regulate their levels in an antagonistic manner. Both proteins are positively correlated with the levels of MIC10 as well as tafazzin, an enzyme required for cardiolipin remodeling. Overexpression of MIC26 induced fragmentation of mitochondria, promoted ROS formation and resulted in impaired mitochondrial respiration. Downregulation of MIC26 induced a decrease in mitochondrial oxygen consumption, whereas mitochondrial network morphology and ROS levels remained unaffected. MIC26 depletion led to alterations in mitochondrial ultrastructure and caused a significant reduction in the number of crista junctions. In summary, we show that the human apolipoprotein MIC26 is a bona fide subunit of the MICOS complex and that MIC26 is linked to cardiolipin metabolism and promotes crista junction formation.
authors.affiliation: Mitochondrial Biology, Buchmann Institute of Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Koob
authors.affiliation: Mitochondrial Biology, Buchmann Institute of Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
authors.forename: Miguel
authors.initials: M
authors.lastname: Barrera
authors.affiliation: Institute of Biochemistry and Molecular Biology I, Heinrich Heine University, Medical Faculty, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Ruchika
authors.initials: R
authors.lastname: Anand
authors.affiliation: Mitochondrial Biology, Buchmann Institute of Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany; Institute of Biochemistry and Molecular Biology I, Heinrich Heine University, Medical Faculty, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address: reichert@hhu.de.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Reichert
mesh_terms: D000217:Acyltransferases; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019069:Cell Respiration; D005110:Extracellular Space / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006031:Glycosylation; D006801:Humans; D008322:Mammals / Q000378:metabolism*; D051916:Membrane Cofactor Protein / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008970:Molecular Weight; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C000589295:APOO protein, human; D001053:Apolipoproteins; C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human
keywords: Apolipoproteins; Arteriosclerosis; Cardiolipin metabolism; Crista junctions; MICOS complex; Mitochondria