The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Bart De Strooper - One of the best experts on this subject based on the ideXlab platform.
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PARL the mitochondrial rhomboid protease
Seminars in Cell & Developmental Biology, 2016Co-Authors: Marco Spinazzi, Bart De StrooperAbstract:Abstract The rhomboid family comprises evolutionary conserved intramembrane proteases involved in a wide spectrum of biologically relevant activities. A mitochondrion-localized rhomboid, called PARL in mammals, and conserved in yeast and Drosophila as RBD1/PCP1 and rho-7, respectively, plays an indispensable role in cell homeostasis as illustrated by the severe phenotypes caused by its genetic ablation in the various investigated species. Although several substrates of PARL have been proposed to explain these phenotypes, there remains a lot of controversy in this important area of research. We review here the putative functions and substrates of PARL and its orthologues in different species, highlighting areas of uncertainty, and discuss its potential involvement in some prevalent diseases such as type II diabetes and Parkinson’s disease.
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Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling.
Cell, 2006Co-Authors: Bart De StrooperAbstract:Rhomboids, evolutionarily conserved integral membrane proteases, participate in crucial signaling pathways. Presenilin-associated rhomboid-like (PARL) is an inner mitochondrial membrane rhomboid of unknown function, whose yeast ortholog is involved in mitochondrial fusion. PARL-/- mice display normal intrauterine development but from the fourth postnatal week undergo progressive multisystemic atrophy leading to cachectic death. Atrophy is sustained by increased apoptosis, both in and ex vivo. PARL-/- cells display normal mitochondrial morphology and function but are no longer protected against intrinsic apoptotic death stimuli by the dynamin-related mitochondrial protein OPA1. PARL-/- mitochondria display reduced levels of a soluble, intermembrane space (IMS) form of OPA1, and OPA1 specifically targeted to IMS complements PARL-/- cells, substantiating the importance of PARL in OPA1 processing. PARL-/- mitochondria undergo faster apoptotic cristae remodeling and cytochrome c release. These findings implicate regulated intramembrane proteolysis in controlling apoptosis.
Thomas Langer - One of the best experts on this subject based on the ideXlab platform.
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PARL partitions the lipid transfer protein stard7 between the cytosol and mitochondria
The EMBO Journal, 2018Co-Authors: Shotaro Saita, Thomas Langer, Takashi Tatsuta, Philipp A Lampe, Tim Konig, Yohsuke OhbaAbstract:Abstract Intramembrane‐cleaving peptidases of the rhomboid family regulate diverse cellular processes that are critical for development and cell survival. The function of the rhomboid protease PARL in the mitochondrial inner membrane has been linked to mitophagy and apoptosis, but other regulatory functions are likely to exist. Here, we identify the START domain‐containing protein STARD7 as an intramitochondrial lipid transfer protein for phosphatidylcholine. We demonstrate that PARL‐mediated cleavage during mitochondrial import partitions STARD7 to the cytosol and the mitochondrial intermembrane space. Negatively charged amino acids in STARD7 serve as a sorting signal allowing mitochondrial release of mature STARD7 upon cleavage by PARL. On the other hand, membrane insertion of STARD7 mediated by the TIM23 complex promotes mitochondrial localization of mature STARD7. Mitochondrial STARD7 is necessary and sufficient for the accumulation of phosphatidylcholine in the inner membrane and for the maintenance of respiration and cristae morphogenesis. Thus, PARL preserves mitochondrial membrane homeostasis via STARD7 processing and is emerging as a critical regulator of protein localization between mitochondria and the cytosol.
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PARL mediates smac proteolytic maturation in mitochondria to promote apoptosis
Nature Cell Biology, 2017Co-Authors: Shotaro Saita, Kai Uwe Fiedler, Saskia A Venne, René P. Zahedi, Hamid Kashkar, Hendrik Nolte, Marcus Kruger, Thomas LangerAbstract:Saita et al. show that PARL cleaves Smac (also known as DIABLO) to generate an IAP-binding motif required for its apoptotic activity, identifying PARL-mediated Smac processing as a pro-apoptotic mitochondrial pathway.
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PARL mediates smac proteolytic maturation in mitochondria to promote apoptosis
Nature Cell Biology, 2017Co-Authors: Shotaro Saita, Kai Uwe Fiedler, Saskia A Venne, René P. Zahedi, Hamid Kashkar, Hendrik Nolte, Marcus Kruger, Thomas LangerAbstract:Mitochondria drive apoptosis by releasing pro-apoptotic proteins that promote caspase activation in the cytosol. The rhomboid protease PARL, an intramembrane cleaving peptidase in the inner membrane, regulates mitophagy and plays an ill-defined role in apoptosis. Here, we employed PARL-based proteomics to define its substrate spectrum. Our data identified the mitochondrial pro-apoptotic protein Smac (also known as DIABLO) as a PARL substrate. In apoptotic cells, Smac is released into the cytosol and promotes caspase activity by inhibiting inhibitors of apoptosis (IAPs). Intramembrane cleavage of Smac by PARL generates an amino-terminal IAP-binding motif, which is required for its apoptotic activity. Loss of PARL impairs proteolytic maturation of Smac, which fails to bind XIAP. Smac peptidomimetics, downregulation of XIAP or cytosolic expression of cleaved Smac restores apoptosis in PARL-deficient cells. Our results reveal a pro-apoptotic function of PARL and identify PARL-mediated Smac processing and cytochrome c release facilitated by OPA1-dependent cristae remodelling as two independent pro-apoptotic pathways in mitochondria.
Luca Pellegrini - One of the best experts on this subject based on the ideXlab platform.
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A cut short to death: PARL and Opa1 in the regulation of mitochondrial morphology and apoptosis
Cell Death & Differentiation, 2007Co-Authors: Luca Pellegrini, Luca ScorranoAbstract:Mitochondria are crucial amplifiers of death signals. They release cytochrome c and other pro-apoptotic factors required to fully activate effector caspases. This release is accompanied by fragmentation of the mitochondrial reticulum and by remodelling of the internal structure of the organelle. Here we review data supporting the existence of a regulatory network in the inner mitochondrial membrane that includes optic atrophy 1 (Opa1), a dynamin-related protein, and presenilin-associated rhomboid-like (PARL), a rhomboid protease. Opa1 regulates remodelling of the cristae independent of its effect on fusion. Cristae remodelling conversely requires PARL, which participates in the production of a soluble form of Opa1 retrieved together with the integral membrane one in oligomers that are disrupted early during apoptosis. PARL itself is regulated by proteolysis to generate a cleaved form, which in turn modulates the shape of the mitochondrial reticulum. Cleavage of PARL depends on its phosphorylation state around the cleavage site, implicating mitochondrial kinases and phosphatases in the regulation of mitochondrial shape.
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phosphorylation and cleavage of presenilin associated rhomboid like protein PARL promotes changes in mitochondrial morphology
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Danny V Jeyaraju, Marieclaude Letellier, Sirisha Bandaru, Rodolfo Zunino, Eric A Berg, Heidi M Mcbride, Luca PellegriniAbstract:Remodeling of mitochondria is a dynamic process coordinated by fusion and fission of the inner and outer membranes of the organelle, mediated by a set of conserved proteins. In metazoans, the molecular mechanism behind mitochondrial morphology has been recruited to govern novel functions, such as development, calcium signaling, and apoptosis, which suggests that novel mechanisms should exist to regulate the conserved membrane fusion/fission machinery. Here we show that phosphorylation and cleavage of the vertebrate-specific Pβ domain of the mammalian presenilin-associated rhomboid-like (PARL) protease can influence mitochondrial morphology. Phosphorylation of three residues embedded in this domain, Ser-65, Thr-69, and Ser-70, impair a cleavage at position Ser77–Ala78 that is required to initiate PARL-induced mitochondrial fragmentation. Our findings reveal that PARL phosphorylation and cleavage impact mitochondrial dynamics, providing a blueprint to study the molecular evolution of mitochondrial morphology.
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Self-regulated Cleavage of the Mitochondrial Intramembrane-cleaving Protease PARL Yields Pβ, a Nuclear-targeted Peptide
Journal of Biological Chemistry, 2004Co-Authors: Brent J. Passer, Eugene V. Koonin, Luca PellegriniAbstract:Regulated intramembrane proteolysis (RIP) is an emerging paradigm in signal transduction. RIP is mediated by intramembrane-cleaving proteases (I-CliPs), which liberate biologically active nuclear or secreted domains from their membrane-tethered precursor proteins. The yeast Pcp1p/Rbd1p protein is a Rhomboid-like I-CliP that regulates mitochondrial membrane remodeling and fusion through cleavage of Mgm1p, a regulator of these essential activities. Although this ancient function is conserved in PARL (Presenilins-associated Rhomboid-like protein), the mammalian ortholog of Pcp1p/Rbd1p, the two proteins show a strong divergence at their N termini. However, the N terminus of PARL is significantly conserved among vertebrates, particularly among mammals, suggesting that this domain evolved a distinct but still unknown function. Here, we show that the cytosolic N-terminal domain of PARL is cleaved at positions 52-53 (alpha-site) and 77-78 (beta-site). Whereas alpha-cleavage is constitutive and removes the mitochondrial targeting sequence, beta-cleavage appears to be developmentally controlled and dependent on PARL I-CliP activity supplied in trans. The beta-cleavage of PARL liberates Pbeta, a nuclear targeted peptide whose sequence is conserved only in mammals. Thus, in addition to its evolutionarily conserved function in regulating mitochondrial dynamics, PARL might mediate a mammalian-specific, developmentally regulated mitochondria-to-nuclei signaling through regulated proteolysis of its N terminus and release of the Pbeta peptide.
Luca Scorrano - One of the best experts on this subject based on the ideXlab platform.
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the antiapoptotic opa1 PARL couple participates in mitochondrial adaptation to heat shock
Biochimica et Biophysica Acta, 2012Co-Authors: Luiza Sanjuan K Szklarz, Luca ScorranoAbstract:The mitochondria-shaping protein optic atrophy 1 (OPA1) has genetically distinguishable roles in mitochondrial morphology and apoptosis. The latter depends on the presenilin associated rhomboid like (PARL) protease, essential for the accumulation of a soluble intermembrane space form of OPA1 (IMS-OPA1). Here we show that OPA1 and PARL participate in the heat shock response, a stereotypical cellular process of adaptation to thermal stress. Upon heat shock, long forms of OPA1 are lost and mitochondria fragment. However, mitochondrial fusion is dispensable to maintain viability, whereas IMS-OPA1 is required. Upon conditioning—a process of mild heat shock and recovery—IMS-OPA1 accumulates, OPA1 oligomers increase and mitochondria release less cytochrome c, ultimately resulting in cellular resistance to subsequent apoptotic inducers. In PARL−/− cells accumulation of IMS-OPA1 is blunted and conditioning fails to protect from cytochrome c release and apoptosis. Thus, the OPA1/PARL dependent pathway of cristae remodeling is implicated in heat shock. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).
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A cut short to death: PARL and Opa1 in the regulation of mitochondrial morphology and apoptosis
Cell Death & Differentiation, 2007Co-Authors: Luca Pellegrini, Luca ScorranoAbstract:Mitochondria are crucial amplifiers of death signals. They release cytochrome c and other pro-apoptotic factors required to fully activate effector caspases. This release is accompanied by fragmentation of the mitochondrial reticulum and by remodelling of the internal structure of the organelle. Here we review data supporting the existence of a regulatory network in the inner mitochondrial membrane that includes optic atrophy 1 (Opa1), a dynamin-related protein, and presenilin-associated rhomboid-like (PARL), a rhomboid protease. Opa1 regulates remodelling of the cristae independent of its effect on fusion. Cristae remodelling conversely requires PARL, which participates in the production of a soluble form of Opa1 retrieved together with the integral membrane one in oligomers that are disrupted early during apoptosis. PARL itself is regulated by proteolysis to generate a cleaved form, which in turn modulates the shape of the mitochondrial reticulum. Cleavage of PARL depends on its phosphorylation state around the cleavage site, implicating mitochondrial kinases and phosphatases in the regulation of mitochondrial shape.
Marius K Lemberg - One of the best experts on this subject based on the ideXlab platform.
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insights into the catalytic properties of the mitochondrial rhomboid protease PARL
Journal of Biological Chemistry, 2021Co-Authors: Laine Lysyk, Marius K Lemberg, Raelynn Brassard, Elena Arutyunova, Verena Siebert, Zhenze Jiang, Emmanuella Takyi, Melissa Morrison, Howard S Young, Anthony J OdonoghueAbstract:Abstract The rhomboid protease PARL is a critical regulator of mitochondrial homeostasis through its cleavage of substrates such as PINK1, PGAM5, and Smac/Diablo, which have crucial roles in mitochondrial quality control and apoptosis. However, the catalytic properties of PARL, including the effect of lipids on the protease, have never been characterized in vitro. To address this, we isolated human PARL expressed in yeast and used FRET-based kinetic assays to measure proteolytic activity in vitro. We show PARL activity in detergent is enhanced by cardiolipin, a lipid enriched in the mitochondrial inner membrane. Significantly higher turnover rates were observed for PARL reconstituted in proteoliposomes, with Smac/Diablo being cleaved most rapidly at a rate of 1 min-1. In contrast, PGAM5 is cleaved with the highest efficiency (kcat/KM) compared to PINK1 and Smac/Diablo. In proteoliposomes, a truncated β-cleavage form of PARL, a physiological form known to affect mitochondrial fragmentation, is more active than the full-length enzyme for hydrolysis of PINK1, PGAM5 and Smac/Diablo. Multiplex profiling of 228 peptides reveals that PARL prefers substrates with a bulky side chain such as Phe in P1, which is distinct from the preference for small side chain residues typically found with bacterial rhomboid proteases. This study using recombinant PARL provides fundamental insights into its catalytic activity and substrate preferences that enhance our understanding of its role in mitochondrial function and has implications for specific inhibitor design.
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insights into the catalytic properties of the mitochondrial rhomboid protease PARL
bioRxiv, 2020Co-Authors: Laine Lysyk, Marius K Lemberg, Raelynn Brassard, Elena Arutyunova, Verena Siebert, Zhenze Jiang, Emmanuella Takyi, Melissa Morrison, Howard S Young, Anthony J OdonoghueAbstract:Abstract The rhomboid protease PARL is a critical regulator of mitochondrial homeostasis through its cleavage of substrates such as PINK1, PGAM5, and Smac, which have crucial roles in mitochondrial quality control and apoptosis. To gain insight into the catalytic properties of the PARL protease, we expressed human PARL in yeast and used FRET-based kinetic assays to measure proteolytic activity in vitro. We show PARL activity in detergent is enhanced by cardiolipin. Significantly higher turnover rates are observed for PARL reconstituted in proteoliposomes, with Smac being cleaved most rapidly at a rate of 1 min−1. PGAM5 is cleaved with the highest efficiency compared to PINK1 and Smac. In proteoliposomes, a truncated β-cleavage form of PARL is more active than the full-length enzyme for hydrolysis of PINK1, PGAM5 and Smac. Multiplex substrate profiling reveals a substrate preference for PARL with a bulky side chain Phe in P1, which is distinct from small side chain residues typically found with bacterial rhomboid proteases. This study using recombinant PARL provides fundamental insights into its catalytic activity and substrate preferences.
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The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking
Journal of neurochemistry, 2011Co-Authors: Cathrin Meissner, Dennis J. Selkoe, Holger Lorenz, Andreas Weihofen, Marius K LembergAbstract:Intramembrane proteolysis is a conserved mechanism that regulates a variety of cellular processes ranging from transcription control to signaling. In mitochondria, the inner membrane rhomboid protease PARL has been implicated in the control of life span and apoptosis by a so far uncharacterized mechanism. Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. Upon depolarization of the mitochondrial membrane potential, the canonical import of Pink1 and PARL-catalyzed processing is blocked, leading to accumulation of the Pink1 precursor. As targeting of this precursor to the outer mitochondrial membrane has been shown to trigger mitophagy, we suggest that the PARL-catalyzed removal of the Pink1 signal sequence in the canonical import pathway acts as a cellular checkpoint for mitochondrial integrity. Furthermore, we show that two Parkinson's disease-causing mutations decrease the processing of Pink1 by PARL, with attendant implications for pathogenesis.
