m‐AAA protease‐driven membrane dislocation allows intramembrane cleavage by rhomboid in mitochondria
TLDR
Findings reveal for the first time a non‐proteolytic function of the m‐AAA protease during mitochondrial biogenesis and rationalise the requirement of a preceding step for intramembrane cleavage by rhomboid.Abstract:
Maturation of cytochrome c peroxidase (Ccp1) in mitochondria occurs by the subsequent action of two conserved proteases in the inner membrane: the m-AAA protease, an ATP-dependent protease degrading misfolded proteins and mediating protein processing, and the rhomboid protease Pcp1, an intramembrane cleaving peptidase. Neither the determinants preventing complete proteolysis of certain substrates by the m-AAA protease, nor the obligatory requirement of the m-AAA protease for rhomboid cleavage is currently understood. Here, we describe an intimate and unexpected functional interplay of both proteases. The m-AAA protease mediates the ATP-dependent membrane dislocation of Ccp1 independent of its proteolytic activity. It thereby ensures the correct positioning of Ccp1 within the membrane bilayer allowing intramembrane cleavage by rhomboid. Decreasing the hydrophobicity of the Ccp1 transmembrane segment facilitates its dislocation from the membrane and renders rhomboid cleavage m-AAA protease-independent. These findings reveal for the first time a non-proteolytic function of the m-AAA protease during mitochondrial biogenesis and rationalise the requirement of a preceding step for intramembrane cleavage by rhomboid.read more
Citations
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Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1
Sarah Ehses,Ines Raschke,Giuseppe Mancuso,Andrea Bernacchia,Stefan Geimer,Daniel Tondera,Jean-Claude Martinou,Benedikt Westermann,Elena I. Rugarli,Thomas Langer,Thomas Langer +10 more
TL;DR: The cleavage by OMA1 causes an accumulation of the short OPA1 variants, and the role ofm-AAA proteases in ensuring a balance of long and short Opa1 isoforms is investigated.
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TL;DR: Current knowledge on surveillance strategies that limit mitochondrial damage and ensure cellular integrity and their role in human disease are summarized.
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Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28
Daniela Di Bella,Federico Lazzaro,Alfredo Brusco,Massimo Plumari,Giorgio Battaglia,Annalisa Pastore,Adele Finardi,Claudia Cagnoli,Filippo Tempia,Marina Frontali,Liana Veneziano,Tiziana Sacco,Enrica Boda,Alessandro Brussino,Florian Bonn,Barbara Castellotti,Silvia Baratta,Caterina Mariotti,Cinzia Gellera,Valentina Fracasso,Stefania Magri,Thomas Langer,Paolo Plevani,Stefano Di Donato,Marco Muzi-Falconi,Franco Taroni +25 more
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TL;DR: Versatile functions of ATP-dependent AAA proteases in the inner membrane of mitochondria conduct protein quality surveillance of mitochondrial inner membrane proteins, mediate vectorial protein dislocation from membranes, and, acting as processing enzymes, control ribosome assembly, mitochondrial protein synthesis, and mitochondrial fusion.
References
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Membrane protein degradation by AAA proteases in mitochondria: extraction of substrates from either membrane surface.
Klaus Leonhard,Bernard Guiard,Giovanna Pellecchia,Alexander Tzagoloff,Walter Neupert,Thomas Langer +5 more
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A novel two-step mechanism for removal of a mitochondrial signal sequence involves the mAAA complex and the putative rhomboid protease Pcp1.
TL;DR: Evidence is presented for a new processing pathway, involving novel signal peptidase activities, involving the mAAA complex and the newly identified Pcp1 protein, which belongs to the rhomboid-GlpG superfamily of putative intramembrane peptidases.
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Variable and Tissue-Specific Subunit Composition of Mitochondrial m-AAA Protease Complexes Linked to Hereditary Spastic Paraplegia
TL;DR: It is proposed that the formation of m-AAA proteases with altered substrate specificities leads to axonal degeneration in hereditary spastic paraplegia (HSP), and homo-oligomeric Afg3l2 complexes accumulate, and these complexes can substitute for housekeeping functions of paraplegin-containing m- AAA complexes.
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The formation of respiratory chain complexes in mitochondria is under the proteolytic control of the m‐AAA protease
TL;DR: An overlapping substrate specificity of the subunits of the m‐AAA protease is revealed and this results explain the impaired assembly of respiratory chain complexes by defects in expression of intron‐containing genes in mitochondria lacking m‐ AAA protease.
Journal ArticleDOI
The molecular architecture of the metalloprotease FtsH.
TL;DR: The crystal structure of a soluble FtsH construct that is functional in caseinolytic and ATPase assays is reported and suggests a possible translocation mechanism of the target polypeptide chain into the interior of the molecule where the proteolytic sites are located.