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Journal ArticleDOI

m‐AAA protease‐driven membrane dislocation allows intramembrane cleavage by rhomboid in mitochondria

24 Jan 2007-The EMBO Journal (European Molecular Biology Organization)-Vol. 26, Iss: 2, pp 325-335

TL;DR: 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.

AbstractMaturation 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.

Topics: Rhomboid protease (70%), Rhomboid (59%), Proteases (57%), Protease (56%)

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Citations
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Journal ArticleDOI
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.
Abstract: Mitochondrial fusion depends on the dynamin-like guanosine triphosphatase OPA1, whose activity is controlled by proteolytic cleavage. Dysfunction of mitochondria induces OPA1 processing and results in mitochondrial fragmentation, allowing the selective removal of damaged mitochondria. In this study, we demonstrate that two classes of metallopeptidases regulate OPA1 cleavage in the mitochondrial inner membrane: isoenzymes of the adenosine triphosphate (ATP)-dependent matrix AAA (ATPase associated with diverse cellular activities [m-AAA]) protease, variable assemblies of the conserved subunits paraplegin, AFG3L1 and -2, and the ATP-independent peptidase OMA1. Functionally redundant isoenzymes of the m-AAA protease ensure the balanced accumulation of long and short isoforms of OPA1 required for mitochondrial fusion. The loss of AFG3L2 in mouse tissues, down-regulation of AFG3L1 and -2 in mouse embryonic fibroblasts, or the expression of a dominant-negative AFG3L2 variant in human cells decreases the stability of long OPA1 isoforms and induces OPA1 processing by OMA1. Moreover, cleavage by OMA1 causes the accumulation of short OPA1 variants if mitochondrial DNA is depleted or mitochondrial activities are impaired. Our findings link distinct peptidases to constitutive and induced OPA1 processing and shed new light on the pathogenesis of neurodegenerative disorders associated with mutations in m-AAA protease subunits.

459 citations


Cites background from "m‐AAA protease‐driven membrane disl..."

  • ...A similar nonproteolytic activity has been assigned to the m-AAA protease during the biogenesis of yeast cytochrome c peroxidase (Tatsuta et al., 2007)....

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Journal ArticleDOI
TL;DR: Current knowledge on surveillance strategies that limit mitochondrial damage and ensure cellular integrity and their role in human disease are summarized.
Abstract: Dysfunction of mitochondria has severe cellular consequences and is linked to ageing and neurodegeneration in human. Several surveillance strategies have evolved that limit mitochondrial damage and ensure cellular integrity. Intraorganellar proteases conduct protein quality control and exert regulatory functions, membrane fusion and fission allow mitochondrial content mixing within a cell, and the autophagic degradation of severely damaged mitochondria protects against apoptosis. Here, we will summarize the current knowledge on these surveillance strategies and their role in human disease.

457 citations


Cites background from "m‐AAA protease‐driven membrane disl..."

  • ...Rhomboid cleavage depends on the ATP-dependent membrane dislocation of Ccp1 by the m-AAA protease but not on its proteolytic activity (Tatsuta et al, 2007)....

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Journal ArticleDOI
TL;DR: The data demonstrate that Cd perturbs the DNA methylation status through the involvement of a specific methyltransferase, linked to nuclear chromatin reconfiguration likely to establish a new balance of expressed/repressed chromatin.
Abstract: In mammals, cadmium is widely considered as a non-genotoxic carcinogen acting through a methylation-dependent epigenetic mechanism. Here, the effects of Cd treatment on the DNA methylation patten are examined together with its effect on chromatin reconfiguration in Posidonia oceanica. DNA methylation level and pattern were analysed in actively growing organs, under short- (6 h) and long- (2 d or 4 d) term and low (10 mM) and high (50 mM) doses of Cd, through a Methylation-Sensitive Amplification Polymorphism technique and an immunocytological approach, respectively. The expression of one member of the CHROMOMETHYLASE (CMT) family, a DNA methyltransferase, was also assessed by qRT-PCR. Nuclear chromatin ultrastructure was investigated by transmission electron microscopy. Cd treatment induced a DNA hypermethylation, as well as an up-regulation of CMT, indicating that de novo methylation did indeed occur. Moreover, a high dose of Cd led to a progressive heterochromatinization of interphase nuclei and apoptotic figures were also observed after long-term treatment. The data demonstrate that Cd perturbs the DNA methylation status through the involvement of a specific methyltransferase. Such changes are linked to nuclear chromatin reconfiguration likely to establish a new balance of expressed/repressed chromatin. Overall, the data show an epigenetic basis to the mechanism underlying Cd toxicity in plants.

381 citations


Cites background from "m‐AAA protease‐driven membrane disl..."

  • ...These families of proteases have previously been noted to operate in the same network (Tatsuta et al., 2007): Ccp1 is a nuclear-encoded protein targeted to the mitochondrion intermembrane space by a bipartite presequence, the latter being cleaved first by ATP-dependent, intramembrane Yta10/12 peptidases (Esser et al....

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Journal ArticleDOI
TL;DR: This work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegenersation.
Abstract: Autosomal dominant spinocerebellar ataxias (SCAs) are genetically heterogeneous neurological disorders characterized by cerebellar dysfunction mostly due to Purkinje cell degeneration. Here we show that AFG3L2 mutations cause SCA type 28. Along with paraplegin, which causes recessive spastic paraplegia, AFG3L2 is a component of the conserved m-AAA metalloprotease complex involved in the maintenance of the mitochondrial proteome. We identified heterozygous missense mutations in five unrelated SCA families and found that AFG3L2 is highly and selectively expressed in human cerebellar Purkinje cells. m-AAA-deficient yeast cells expressing human mutated AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment and deficiency of respiratory chain complex IV. Structure homology modeling indicates that the mutations may affect AFG3L2 substrate handling. This work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegeneration.

260 citations


Cites background from "m‐AAA protease‐driven membrane disl..."

  • ...if there are any such proteins, or even on ATPase activit...

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Journal ArticleDOI
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.
Abstract: Cell survival depends on essential processes in mitochondria. Various proteases within these organelles regulate mitochondrial biogenesis and ensure the complete degradation of excess or damaged proteins. Many of these proteases are highly conserved and ubiquitous in eukaryotic cells. They can be assigned to three functional classes: processing peptidases, which cleave off mitochondrial targeting sequences of nuclearly encoded proteins and process mitochondrial proteins with regulatory functions; ATP-dependent proteases, which either act as processing peptidases with regulatory functions or as quality-control enzymes degrading non-native polypeptides to peptides; and oligopeptidases, which degrade these peptides and mitochondrial targeting sequences to amino acids. Disturbances of protein degradation within mitochondria cause severe phenotypes in various organisms and can lead to the induction of apoptotic programmes and cell-specific neurodegeneration in mammals. After an overview of the proteoly...

244 citations


Cites background from "m‐AAA protease‐driven membrane disl..."

  • ...Strikingly, although strictly dependent on the presence of the m-AAA protease, maturation of Ccp1 by rhomboid was observed in yeast cells harboring a proteolytically inactive variant of the m-AAA protease (Tatsuta et al., 2007)....

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  • ...Subsequent experiments revealed that the m-AAA protease is required to mediate the ATP-dependent vectorial dislocation of Ccp1 from the membrane bilayer (Figure 4B) (Tatsuta et al., 2007)....

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  • ...yeast cells harboring a proteolytically inactive variant of the m-AAA protease (Tatsuta et al., 2007)....

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  • ...A recent study on the processing of cytochrome c peroxidase (Ccp1) directly demonstrated the ability of the m-AAA protease to mediate vectorial membrane dislocation of proteins in an ATP-dependent reaction (see below) (Tatsuta et al., 2007)....

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  • ...A bipartite presequence targets Ccp1 to the mitochondrial intermembrane space and is removed by rhomboid after its vectorial membrane dislocation by the ATP-dependent m-AAA protease (Tatsuta et al., 2007) (see below)....

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References
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Journal ArticleDOI
TL;DR: The structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction are reviewed.
Abstract: The AAA+ (ATPases associated with various cellular activities) family is a large and functionally diverse group of enzymes that are able to induce conformational changes in a wide range of substrate proteins. The family's defining feature is a structurally conserved ATPase domain that assembles into oligomeric rings and undergoes conformational changes during cycles of nucleotide binding and hydrolysis. Here, we review the structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction.

1,074 citations


"m‐AAA protease‐driven membrane disl..." refers background in this paper

  • ...This loop contains an aromatichydrophobic-glycine motif (FVG in Yta10 and Yta12), which is conserved within AAAþ proteins (Figure 7A) and has been linked to substrate translocation in other AAA proteins (Sauer et al, 2004; Hanson and Whiteheart, 2005)....

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  • ...At the same time, they conduct the quality surveillance of cellular proteins and degrade misfolded proteins to peptides (Sauer et al, 2004; Ciechanover, 2005; Hanson and Whiteheart, 2005)....

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  • ...Conserved residues in the pore loop are essential for Ccp1 processing Most AAAþ proteins form hexameric ring structures that allow substrates to enter the central channel (Sauer et al, 2004; Hanson and Whiteheart, 2005)....

    [...]

  • ...This loop contains an aromatichydrophobic-glycine motif (FVG in Yta10 and Yta12), which is conserved within AAA proteins (Figure 7A) and has been linked to substrate translocation in other AAA proteins (Sauer et al, 2004; Hanson and Whiteheart, 2005)....

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  • ...Ccp1 processing Most AAA proteins form hexameric ring structures that allow substrates to enter the central channel (Sauer et al, 2004; Hanson and Whiteheart, 2005)....

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Journal ArticleDOI
Abstract: How the genetic code is translated into proteins was a key focus of biological research before the 1980s, but how these proteins are degraded remained a neglected area With the discovery of the lysosome, it was suggested that cellular proteins are degraded in this organelle However, several independent lines of experimental evidence strongly indicated that non-lysosomal pathways have an important role in intracellular proteolysis, although their identity and mechanisms of action remained obscure The discovery of the ubiquitin–proteasome system resolved this enigma

946 citations


Journal ArticleDOI
TL;DR: M mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ‐dependent manner through proteolytic cleavage of Mgm1, the yeast homolog of O PA1.
Abstract: The dynamin-like GTPase OPA1, a causal gene product of human dominant optic atrophy, functions in mitochondrial fusion and inner membrane remodeling. It has several splice variants and even a single variant is found as several processed forms, although their functional significance is unknown. In yeast, mitochondrial rhomboid protease regulates mitochondrial function and morphology through proteolytic cleavage of Mgm1, the yeast homolog of OPA1. We demonstrate that OPA1 variants are synthesized with a bipartite-type mitochondrial targeting sequence. During import, the matrix-targeting signal is removed and processed forms (L-isoforms) are anchored to the inner membrane in type I topology. L-isoforms undergo further processing in the matrix to produce S-isoforms. Knockdown of OPA1 induced mitochondrial fragmentation, whose network morphology was recovered by expression of L-isoform but not S-isoform, indicating that only L-isoform is fusion-competent. Dissipation of membrane potential, expression of m-AAA protease paraplegin, or induction of apoptosis stimulated this processing along with the mitochondrial fragmentation. Thus, mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ-dependent manner.

742 citations


"m‐AAA protease‐driven membrane disl..." refers background in this paper

  • ...Of note, proteolytic processing of the Mgm1 homologue OPA1 in mammalian cells has recently been linked to an m-AAA protease (Ishihara et al, 2006)....

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Journal ArticleDOI
TL;DR: The very large peptide bond ASP, -96 +/- 6 cal/mol/A2, profoundly affects the results of computational comparisons of protein stability which use ASPs derived from octanol-water partitioning data.
Abstract: Octanol-to-water solvation free energies of acetyl amino amides (Ac-X-amides) [Fauchere, J.L., & Pliska, V. (1983) Eur. J. Med. Chem. --Chim. Ther. 18,369] form the basis for computational comparisons of protein stabilities by means of the atomic solvation parameter formalism of Eisenberg and McLachlan [(1986) Nature 319, 199]. In order to explore this approach for more complex systems, we have determined by octanol-to-water partitioning the solvation energies of (1) the guest (X) side chains in the host-guest pentapeptides AcWL-X-LL, (2) the carboxy terminus of the pentapeptides, and (3) the peptide bonds of the homologous series of peptides AcWLm (m = 1-6). Solvation parameters were derived from the solvation energies using estimates of the solvent-accessible surface areas (ASA) obtained from hard-sphere Monte Carlo simulations. The measurements lead to a side chain solvation-energy scale for the pentapeptides and suggest the need for modifying the Asp, Glu, and Cys values of the "Fauchere-Pliska" solvation-energy scale fro the Ac-X-amides. We find that the unfavorable solvation energy of nonpolar residues can be calculated accurately by a solvation parameter of 22.8 +/- 0.8 cal/mol/A2, which agrees satisfactorily with the AC-X-amide data and thereby validates the Monte Carlo ASA results. Unlike the Ac-X-amide data, the apparent solvation energies of the uncharged polar residues are also largely unfavorable. This unexpected finding probably results, primarily, from differences in conformation and hydrogen bonding in octanol and buffer but may also be due to the additional flaking peptide bonds of the pentapeptides. The atomic solvation parameter (ASP) for the peptide bond is comparable to the ASP of the charged carboxy terminus which is an order of magnitude larger than the ASP of the uncharged polar side chains of the Ac-X-amides. The very large peptide bond ASP, -96 +/- 6 cal/mol/A2, profoundly affects the results of computational comparisons of protein stability which use ASPs derived from octanol-water partitioning data.

509 citations


"m‐AAA protease‐driven membrane disl..." refers methods in this paper

  • ...We determined the hydrophobicity of this region using the membrane protein explorer (MPEx) programme, which is based on experimentally derived Wimley–White hydropathy scale (Wimley et al, 1996)....

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Journal ArticleDOI
01 Oct 2004-Cell
TL;DR: Exciting progress has been made in understanding how AAA(+) machines recognize specific proteins as targets and then carry out ATP-dependent dismantling of the tertiary and/or quaternary structure of these molecules during the processes of protein degradation and the disassembly of macromolecular complexes.
Abstract: Machines of protein destruction—including energy-dependent proteases and disassembly chaperones of the AAA+ ATPase family—function in all kingdoms of life to sculpt the cellular proteome, ensuring that unnecessary and dangerous proteins are eliminated and biological responses to environmental change are rapidly and properly regulated. Exciting progress has been made in understanding how AAA+ machines recognize specific proteins as targets and then carry out ATP-dependent dismantling of the tertiary and/or quaternary structure of these molecules during the processes of protein degradation and the disassembly of macromolecular complexes.

442 citations


"m‐AAA protease‐driven membrane disl..." refers background in this paper

  • ...Conserved residues in the pore loop are essential for Ccp1 processing Most AAAþ proteins form hexameric ring structures that allow substrates to enter the central channel (Sauer et al, 2004; Hanson and Whiteheart, 2005)....

    [...]

  • ...At the same time, they conduct the quality surveillance of cellular proteins and degrade misfolded proteins to peptides (Sauer et al, 2004; Ciechanover, 2005; Hanson and Whiteheart, 2005)....

    [...]

  • ...ATP-dependent unfolding of substrates allows substrate entry into barrel-like proteolytic chambers and results in complete degradation (Sauer et al, 2004)....

    [...]

  • ...This loop contains an aromatichydrophobic-glycine motif (FVG in Yta10 and Yta12), which is conserved within AAAþ proteins (Figure 7A) and has been linked to substrate translocation in other AAA proteins (Sauer et al, 2004; Hanson and Whiteheart, 2005)....

    [...]