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• W2921446987 abstract "Porin is crucial for metabolite flux in mitochondria. In this issue of Molecular Cell, Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar and Ellenrieder et al., 2019Ellenrieder L. Dieterle M.P. Doan K.N. Mårtensson C.U. Floerchinger A. Campo M.L. Pfanner N. Becker T. Dual role of mitochondrial Porin in metabolite transport across the outer membrane and protein transfer to the inner membrane.Mol. Cell. 2019; 73 (this issue): 1056-1065Scopus (36) Google Scholar describe an unexpected role for Porin in mitochondrial protein import by regulating the oligomeric state of the major protein import gate, the TOM complex, and the inner membrane insertion of metabolite carriers. Porin is crucial for metabolite flux in mitochondria. In this issue of Molecular Cell, Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar and Ellenrieder et al., 2019Ellenrieder L. Dieterle M.P. Doan K.N. Mårtensson C.U. Floerchinger A. Campo M.L. Pfanner N. Becker T. Dual role of mitochondrial Porin in metabolite transport across the outer membrane and protein transfer to the inner membrane.Mol. Cell. 2019; 73 (this issue): 1056-1065Scopus (36) Google Scholar describe an unexpected role for Porin in mitochondrial protein import by regulating the oligomeric state of the major protein import gate, the TOM complex, and the inner membrane insertion of metabolite carriers. Protein import into mitochondria is critical for mitochondrial function and cell fitness. 99% of mitochondrial proteins are translated in the cytosol and imported through one essential mitochondrial import gate, the translocase of the outer membrane (the TOM complex). TOM is a multi-subunit complex made up of three main receptor proteins, Tom20, Tom22, and Tom70; three small channel-modulating subunits Tom5, Tom6, and Tom7; and the key import channel Tom40 (Pfanner et al., 2019Pfanner N. Warscheid B. Wiedemann N. Mitochondrial proteins: from biogenesis to functional networks.Nat. Rev. Mol. Cell Biol. 2019; 2019: 9Google Scholar). Previous studies have suggested that the TOM complex exists in many different states that alter the channel components (Shiota et al., 2015Shiota T. Imai K. Qiu J. Hewitt V.L. Tan K. Shen H.-H. Sakiyama N. Fukasawa Y. Hayat S. Kamiya M. et al.Molecular architecture of the active mitochondrial protein gate.Science. 2015; 349: 1544-1548Crossref PubMed Scopus (130) Google Scholar, Gornicka et al., 2014Gornicka A. Bragoszewski P. Chroscicki P. Wenz L.-S. Schulz C. Rehling P. Chacinska A. A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria.Mol. Biol. Cell. 2014; 25: 3999-4009Crossref PubMed Scopus (38) Google Scholar). A combination of the detailed mapping of the architecture of the TOM complex by site-specific crosslinking (Shiota et al., 2015Shiota T. Imai K. Qiu J. Hewitt V.L. Tan K. Shen H.-H. Sakiyama N. Fukasawa Y. Hayat S. Kamiya M. et al.Molecular architecture of the active mitochondrial protein gate.Science. 2015; 349: 1544-1548Crossref PubMed Scopus (130) Google Scholar) and the determination of the structure of the Neurospora Crassa TOM complex (Bausewein et al., 2017Bausewein T. Mills D.J. Langer J.D. Nitschke B. Nussberger S. Kühlbrandt W. Cryo-EM structure of the TOM core complex from Neurospora crassa.Cell. 2017; 170: 693-700.e7Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar) indicated that the TOM complex adopts both a trimeric and a dimeric oligomeric structure. The abundant outer membrane channel Porin is a voltage-dependent anion channel whose role in transporting metabolites and ions is well established but its role in protein import into mitochondria was hitherto unknown. Now, two papers by the Endo and Pfanner groups, respectively, elegantly describe a novel role for Porin whereby this protein plays a critical role in the transition of the TOM complex between the trimer and dimer states and directly impacts on the pathway that inserts the metabolite carrier proteins in the inner mitochondrial membrane (Figure 1; Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, Ellenrieder et al., 2019Ellenrieder L. Dieterle M.P. Doan K.N. Mårtensson C.U. Floerchinger A. Campo M.L. Pfanner N. Becker T. Dual role of mitochondrial Porin in metabolite transport across the outer membrane and protein transfer to the inner membrane.Mol. Cell. 2019; 73 (this issue): 1056-1065Scopus (36) Google Scholar). Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar provide a comprehensive analysis of a novel role for yeast Porin in regulating the dynamic transition of the TOM complex from a trimeric to a dimeric state. Although such a dynamic behavior of the TOM complex has been previously suggested (Model et al., 2002Model K. Prinz T. Ruiz T. Radermacher M. Krimmer T. Kühlbrandt W. Pfanner N. Meisinger C. Protein translocase of the outer mitochondrial membrane: role of import receptors in the structural organization of the TOM complex.J. Mol. Biol. 2002; 316: 657-666Crossref PubMed Scopus (104) Google Scholar), Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar describe a molecular handle and mechanistic framework to this process. Porin regulates this dynamic transition through an interaction with the major Tom receptor Tom22, which is normally present in the trimeric form of the TOM channel. Sequestration of Tom22 off the trimer favors the dimeric form of the TOM channel, which favors the import of a subset of mitochondrial proteins including substrates of the Mia40 import pathway. A strain lacking Porin is severely depleted in the small Tim chaperone proteins Tim9 and Tim10, which are dependent on Mia40 for their import. Gornicka et al., 2014Gornicka A. Bragoszewski P. Chroscicki P. Wenz L.-S. Schulz C. Rehling P. Chacinska A. A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria.Mol. Biol. Cell. 2014; 25: 3999-4009Crossref PubMed Scopus (38) Google Scholar previously showed that Mia40 substrates do not require Tom22 for import, reinforcing the work of Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar. The TOM receptor Tom6 stabilizes the Tom22 receptor, preventing its dissociation from the trimeric TOM complex by inserting itself between two Tom40 channels. Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar exemplify this dynamic process during the cell cycle as interactions between Tom6 and Tom40, as well as Porin and Tom22, change depending on the cell cycle stage. During M phase, Tom6 interacts with Tom40 to stabilize the trimeric Tom complex, thus retaining Tom22. During S phase, Porin interacts with Tom22 to favor the dimeric complex. The results of Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar highlight a novel role for Porin as a key controller of the dynamic transition of the TOM complex that is critical for this machinery to recognize and transport different preproteins efficiently. Additionally, they provide new evidence that the dynamic transitions of the TOM channel must be seen in the context of a cell-cycle-regulated process through both the Tom6-Tom40 association and the Porin-Tom22 association. Ellenrieder et al., 2019Ellenrieder L. Dieterle M.P. Doan K.N. Mårtensson C.U. Floerchinger A. Campo M.L. Pfanner N. Becker T. Dual role of mitochondrial Porin in metabolite transport across the outer membrane and protein transfer to the inner membrane.Mol. Cell. 2019; 73 (this issue): 1056-1065Scopus (36) Google Scholar elucidate a novel role for yeast Porin as a coupling factor assisting the transport of metabolite carrier proteins from the outer membrane to the Tim22 insertion machinery of the inner membrane. They show that loss of Porin results in a reduction of several metabolite carriers. Interestingly, the ion flux activity of Porin is not required for the import of the metabolite carriers. The carrier import machinery comprising the Tim22 channel and small Tim chaperone complex Tim9/10 both interact with Porin. The combined results strongly support a role for Porin in the import of the metabolite carriers. Ellenrieder et al., 2019Ellenrieder L. Dieterle M.P. Doan K.N. Mårtensson C.U. Floerchinger A. Campo M.L. Pfanner N. Becker T. Dual role of mitochondrial Porin in metabolite transport across the outer membrane and protein transfer to the inner membrane.Mol. Cell. 2019; 73 (this issue): 1056-1065Scopus (36) Google Scholar go on to dissect the exact stage at which Porin is involved in the well-characterized metabolite carrier import pathway. The two early stages of metabolite carrier import involving ATP-dependent cytosolic chaperones (stage I) and accumulation on the Tom70 receptor (stage II) are unaffected by Porin. By contrast, the later stages of translocation across the intermembrane space (stage III), accumulation at the Tim22 channel (stage IV), and insertion into the inner membrane (stage V) are clearly affected when Porin is deleted. The defect is particularly evident at stage III, suggesting that Porin is involved in the transfer of the metabolite carriers to the inner membrane. This is an intriguing finding as it has been previously shown that the interaction of the carrier preprotein at stage III with the soluble small Tim chaperones in the intermembrane space (IMS) is sufficient to drive the complete insertion of the carriers in in vitro reconstitution and in vivo experiments (Luciano et al., 2001Luciano P. Vial S. Vergnolle M.A. Dyall S.D. Robinson D.R. Tokatlidis K. Functional reconstitution of the import of the yeast ADP/ATP carrier mediated by the TIM10 complex.EMBO J. 2001; 20: 4099-4106Crossref PubMed Scopus (46) Google Scholar, Weinhäupl et al., 2018Weinhäupl K. Lindau C. Hessel A. Wang Y. Schütze C. Jores T. Melchionda L. Schönfisch B. Kalbacher H. Bersch B. et al.Structural basis of membrane protein chaperoning through the mitochondrial intermembrane space.Cell. 2018; 175: 1365-1379.e25Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). The involvement of Porin in this process indicates a more elaborate mechanism than originally thought. Both articles shed new light in the functions of Porin in mitochondria. They demonstrate that Porin is intimately linked to the mitochondrial protein import machineries in a manner independent of its metabolite transport function. Yet, why this intimate link is required for the import of certain proteins is still unclear. Sakaue et al., 2019Sakaue H. Shiota T. Ishizaka N. Kawano S. Tamura Y. Tan K.S. Imai K. Motono C. Hirokawa T. Taki K. et al.Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.Mol. Cell. 2019; 73 (this issue): 1044-1055Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar show that the IMS proteins dependent on Mia40 favor the dimeric TOM complex over the trimeric. They suggest that loss of the Tom22 receptor makes the Tom40 channel more accessible to substrates that depend on disulphide bond formation for their folding. One key question that arises from this study is what sequence or surface determinants are specific to (or more accessible in) the dimeric TOM complex that the IMS proteins recognize to facilitate their import. The physiological significance of the cell-cycle stage-dependent regulation of the TOM complex is also intriguing as this could act as a quality control mechanism to orchestrate the efficient import of all mitochondrial proteins via their preferred TOM complex. Even more surprisingly, the effect of Porin on protein import goes beyond the level of the outer membrane channel dynamics to optimize transfer of carrier precursors across the IMS. Both papers provide exciting data that pave the way for future studies to investigate the nuances that dictate how Porin regulates the oligomeric state of the TOM channel and how it physically aids the import of the metabolite carriers. In broader terms, it will be interesting to investigate whether these unexpected roles of Porin are conserved in mammals as the TOM complex and protein import pathways are linked to human diseases. Dual Role of Mitochondrial Porin in Metabolite Transport across the Outer Membrane and Protein Transfer to the Inner MembraneEllenrieder et al.Molecular CellFebruary 6, 2019In BriefEllenrieder et al. report that the major metabolite channel porin of the mitochondrial outer membrane promotes the import of carrier proteins to the mitochondrial inner membrane. Porin binds carrier precursors in the intermembrane space and recruits the carrier translocase of the inner membrane to facilitate transfer of the precursor proteins. Full-Text PDF Open ArchivePorin Associates with Tom22 to Regulate the Mitochondrial Protein Gate AssemblySakaue et al.Molecular CellFebruary 6, 2019In BriefThe mitochondrial protein entry gate, the TOM complex, undergoes a dynamic conversion between the fully assembled trimer and the dimer lacking Tom22. Mitochondrial porin, Por1, regulates the trimer assembly by chaperoning newly imported Tom22 and dimer-trimer dependent functions of the TOM complex together with Tom6. Full-Text PDF Open Archive" @default.
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• W2921446987 title "The Yeast Voltage-Dependent Anion Channel Porin: More IMPORTant than Just Metabolite Transport" @default.
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