title: The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i-AAA protease YME1L.
abstract: The SPFH (stomatin, prohibitin, flotillin, HflC/K) superfamily is composed of scaffold proteins that form ring-like structures and locally specify the protein-lipid composition in a variety of cellular membranes. Stomatin-like protein 2 (SLP2) is a member of this superfamily that localizes to the mitochondrial inner membrane (IM) where it acts as a membrane organizer. Here, we report that SLP2 anchors a large protease complex composed of the rhomboid protease PARL and the i-AAA protease YME1L, which we term the SPY complex (for SLP2-PARL-YME1L). Association with SLP2 in the SPY complex regulates PARL-mediated processing of PTEN-induced kinase PINK1 and the phosphatase PGAM5 in mitochondria. Moreover, SLP2 inhibits the stress-activated peptidase OMA1, which can bind to SLP2 and cleaves PGAM5 in depolarized mitochondria. SLP2 restricts OMA1-mediated processing of the dynamin-like GTPase OPA1 allowing stress-induced mitochondrial hyperfusion under starvation conditions. Together, our results reveal an important role of SLP2 membrane scaffolds for the spatial organization of IM proteases regulating mitochondrial dynamics, quality control, and cell survival.
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany.
authors.forename: Timothy
authors.initials: T
authors.lastname: Wai
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Saita
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nolte
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Müller
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: König
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Richter-Dennerlein
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sprenger
authors.affiliation: Microbiome and Disease Tolerance Centre, Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Madrenas
authors.affiliation: Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Mareike
authors.initials: M
authors.lastname: Mühlmeister
authors.affiliation: Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ulrich
authors.identifier: 0000-0003-1869-6811
authors.initials: U
authors.lastname: Brandt
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and University of Cologne, Cologne, Germany thomas.langer@uni-koeln.de.|Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.identifier: 0000-0003-1250-1462
authors.initials: T
authors.lastname: Langer
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D001798:Blood Proteins; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D008666:Metalloendopeptidases; D045726:Metalloproteases; D024101:Mitochondrial Proteins; D010447:Peptide Hydrolases; D010749:Phosphoprotein Phosphatases; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C406287:STOML2 protein, human; C529563:PGAM5 protein, human; C485223:PARL protein, human; C410807:YME1L1 protein, human; C477817:molecule metalloprotease-related protein-1, human; C415198:OPA1 protein, human
keywords: OMA1; SLP2; YME1L; membrane scaffold; mitochondria; rhomboid