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• W1926695909 abstract "Focus Review21 February 2012free access Mitochondrial quality control: a matter of life and death for neurons Elena I Rugarli Corresponding Author Elena I Rugarli Institute for Zoology, University of Cologne, Cologne, Germany Center for Molecular Medicine (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Search for more papers by this author Thomas Langer Corresponding Author Thomas Langer Center for Molecular Medicine (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Institute for Genetics, University of Cologne, Cologne, Germany Max-Planck-Institute for Biology of Aging, Cologne, Germany Search for more papers by this author Elena I Rugarli Corresponding Author Elena I Rugarli Institute for Zoology, University of Cologne, Cologne, Germany Center for Molecular Medicine (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Search for more papers by this author Thomas Langer Corresponding Author Thomas Langer Center for Molecular Medicine (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Institute for Genetics, University of Cologne, Cologne, Germany Max-Planck-Institute for Biology of Aging, Cologne, Germany Search for more papers by this author Author Information Elena I Rugarli 1,2 and Thomas Langer 2,3,4 1Institute for Zoology, University of Cologne, Cologne, Germany 2Center for Molecular Medicine (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany 3Institute for Genetics, University of Cologne, Cologne, Germany 4Max-Planck-Institute for Biology of Aging, Cologne, Germany *Corresponding authors: Biocenter, Universität zu Köln, Zülpicher Strasse 47b, 50674 Köln, Germany. Tel.: +49 221 470 8290; Fax: +49 221 470 8590; E-mail: [email protected] für Genetik, Universität zu Köln, Zülpicher Strasse 47a, 50674 Köln, Germany. Tel.: +49 221 470 4876; Fax: +49 221 470 6749; E-mail: [email protected] The EMBO Journal (2012)31:1336-1349https://doi.org/10.1038/emboj.2012.38 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info Neuronal survival critically depends on the integrity and functionality of mitochondria. A hierarchical system of cellular surveillance mechanisms protects mitochondria against stress, monitors mitochondrial damage and ensures the selective removal of dysfunctional mitochondrial proteins or organelles. Mitochondrial proteases emerge as central regulators that coordinate different quality control (QC) pathways within an interconnected network of mechanisms. A failure of this system causes neuronal loss in a steadily increasing number of neurodegenerative disorders, which include Parkinson's disease, spinocerebellar ataxia, spastic paraplegia and peripheral neuropathies. Here, we will discuss the role of the mitochondrial QC network for neuronal survival and neurodegeneration. Introduction Eukaryotic cells have evolved elaborate and powerful quality control (QC) systems to detect and eliminate damage in several compartments. The complex biogenesis of mitochondria as endosymbiontic organelles and their manifold biological functions render these organelles particularly vulnerable to accumulating damage during cell life. Mitochondria contain their own genome, which encodes 13 polypeptides, 22 tRNAs and 2 rRNAs; yet, the vast majority of mitochondrial proteins are encoded by the nuclear genome, synthesized in the cytoplasm and subsequently imported in the organelle (Larsson, 2010; Schmidt et al, 2010). Although nuclear-mitochondria communication systems coordinate the expression of the two genomes, a possible imbalance between nuclear-encoded and mitochondrial-encoded respiratory chain subunits and the accumulation of misfolded polypeptides is a risk that mitochondria continuously face. Mitochondria are the sites of ATP production through oxidative phosphorylation, but as a by-product they are exposed to high concentrations of reactive oxygen species (ROS), which can induce protein modifications, lipid peroxidation and DNA damage (Murphy et al, 2011). Finally, mitochondria are intimately connected to the endoplasmic reticulum and play an important role in cellular Ca2+ homeostasis (Csordas et al, 2010). Mitochondrial Ca2+ uptake and release regulates several processes, such as ATP production and hormone metabolism, while an overload of mitochondria with Ca2+ can in turn trigger apoptosis and cell death (Giorgi et al, 2008). Cells have solved the challenge of maintaining the functionality of mitochondria by establishing rigorous surveillance systems that allow it to detect mitochondrial dysfunction and to eliminate the damage. Studies in recent years unravelled a hierarchical system of interdependent QC mechanisms that ensure cell survival (Figure 1A; Tatsuta and Langer, 2008). The first line of defense operates within mitochondria and consists of an ‘army’ of chaperones and proteases, which promote folding of newly imported preproteins, protect mitochondrial proteins against heat stress and degrade irreversibly damaged polypeptides (intraorganellar QC system). ATP-dependent proteases are able to recognize specifically misfolded polypeptides and degrade them to peptides, which are subsequently exported from the organelle or further degraded to amino acids by the action of oligopeptidases (Figure 1B). The i-AAA (intermembrane space-ATPase Associated with various cellular Activities) and m-AAA (matrix-ATPase Associated with various cellular Activities) proteases are located in the inner membrane and expose their catalytic sites to opposite membrane surfaces, while Lon and ClpXP proteases are active in the matrix. Many but not all proteases with a role in protein quality surveillance are ATP dependent and utilize the energy derived from ATP hydrolysis to unfold substrate proteins and processively degrade them to peptides (Sauer and Baker, 2011). They harbour an AAA ATPase domain with chaperone-like properties (Leonhard et al, 1999), which is characteristic of the AAA+ family of proteins. Oligomeric, in most cases hexameric, complexes form a proteolytic chamber allowing proteolysis to occur in a sequestered environment. The capacity of the mitochondrial QC system can be adjusted to increased demands, for example, under stress conditions, by a transcriptional programme that induces the nuclear expression of mitochondrial chaperone proteins and proteases (the so-called mitochondrial unfolded protein response, mtUPR) (Zhao et al, 2002; Benedetti et al, 2006). The signal transduction cascade that controls the mtUPR signal has been identified in C. elegans, and is beginning to be unravelled in mammalian cells. Although the nature of the signal triggering the response remains enigmatic, the identification of an ABC transporter with a role in the export of peptides from mitochondria raises the intriguing possibility that peptides generated upon proteolysis within mitochondria play a critical role in this pathway (Young et al, 2001; Haynes et al, 2010). Figure 1.(A) The hierarchical network of mitochondrial QC mechanisms. Intramitochondrial proteases and molecular chaperone proteins maintain mitochondrial proteostasis. Stress conditions induce a transcriptional programme (mitochondrial unfolded protein response, mtUPR) that increases protein levels of chaperones and proteases in mitochondria. Fusion allowing content mixing contributes to mitochondrial integrity and stress-induced mitochondrial hyperfusion may alleviate mild mitochondrial stress. A dysfunction of mitochondria inhibits fusion and triggers fragmentation of the mitochondrial network, which is associated with mitophagy or, under conditions of severe damage, leads to mitochondrial outer membrane permeabilization and apoptosis. (B) Submitochondrial localization of proteases with functions in mitochondrial QC. i-AAA, i-AAA protease; m-AAA, m-AAA protease; OM, outer membrane; IMS, intermembrane space; IM, inner membrane. Download figure Download PowerPoint The second line of defense is concerned with the mitochondrial population of a cell (organellar QC system). Mitochondria form a dynamic network that is maintained by opposing fusion and fission events (Chen and Chan, 2009; Westermann, 2010). The fusion of mitochondrial membranes allows exchange of genetic material and protects against accumulation of damage (Chen et al, 2005, 2010). In stress conditions, for instance during nutrient starvation, oxidative stress, or when cytosolic protein synthesis is impaired, mitochondria respond by hyperfusing (Tondera et al, 2009). Nutrient starvation triggers the inhibition of mitochondrial fission resulting in unopposed fusion (Gomes et al, 2011; Rambold et al, 2011). Stress-induced mitochondrial hyperfusion allows mitochondria to increase ATP production, protects against the autophagic removal of mitochondria (mitophagy) and promotes cell survival. Mitochondrial dysfunction, however, causes the inhibition of mitochondrial fusion. Ongoing fission events lead to a fragmentation of the mitochondrial network, which facilitates the segregation and elimination of dysfunctional organelles through mitophagy. Finally, severe mitochondrial damage results in the release of pro-apoptotic factors like cytochrome c from the mitochondrial intermembrane space inducing the apoptotic programme. Numerous studies have revealed in recent years that mitochondrial QC systems are highly regulated and interdependent and have established an intricate network of responses that ensures cell survival. Here, we will summarize these findings focussing on the central role of mitochondrial proteases for the regulation of mitochondrial QC at all levels. Challenging aspects of mitochondrial QC in neurons Neurons critically rely on mitochondrial function and oxygen supply, since most neuronal ATP is produced by oxidative phosphorylation. High ATP levels are required to sustain axonal transport of macromolecules and organelles such as mitochondria, to maintain ionic gradients and the membrane potential, to load synaptic vesicles with neurotransmitters and to release neurotransmitters into the synaptic cleft. Moreover, synaptic mitochondria are exposed to extensive Ca2+ influx and have a key role to buffer the cytosolic Ca2+ concentration. To fully comprehend the relationship between mitochondria and neuronal function, it is important to consider that neurons are extremely polarized cells, with complex and diverse morphologies, characterized by the extension of long axons and more or less elaborate dendritic trees. These specialized areas have very different energetic demands and require local and fast adaptation of mitochondrial function (Li et al, 2004; MacAskill et al, 2010). Mitochondrial trafficking machineries, which are intimately coupled to mitochondrial dynamics (Misko et al, 2010), ensure mitochondrial delivery and localization to regions of high energy and Ca2+ buffering requirements within neurons (MacAskill and Kittler, 2010). However, the need to transport mitochondria far away from the cell body, where most of mitochondrial biogenesis is believed to occur, has other important consequences. First, mitochondria have a longer half-life in neurons than in other post-mitotic tissues (Menzies and Gold, 1971; Miwa et al, 2008; O'Toole et al, 2008) and in this regard are more likely to accumulate damage. Second, although local translation of a subset of mitochondrial proteins might occur in axons (Kaplan et al, 2009), the import of most newly synthesized proteins involves mitochondria in the cell body. Mitochondria located in the cell periphery thus might become ‘old and out of touch’ and be less efficient in coping with accumulating misfolded polypeptides or Ca2+ overload (Brown et al, 2006). Finally, removal of damaged mitochondria by mitophagy can be a demanding task in neurons. Autophagosomes form in axons, however, as they need to travel all the way back to the cell body to fuse with lysosomes (Wang et al, 2006), it is possible that this energy-dependent process could be impaired in the face of mitochondrial dysfunction. The aforementioned processes are linked to and influenced by mitochondrial dynamics. The mitochondrial network is elongated in dendrites and close to the cell body, but tends to be more fragmented in axons, probably to enhance transport of mitochondria along great distances (Popov et al, 2005). Consistently, fission occurs in axons more frequently than fusion, and in general both events seem to happen at a lower rate than in other cell types (Berman et al, 2009). Moreover, the rate of fission to fusion events changes with the age of neurons (Arnold et al, 2011). In conclusion, though neurons possess the same mitochondrial QC systems as other cells, the challenges these systems face are more arduous given the high mitochondrial demands, increasing the risk of accumulating damage, and spatial restraints beset by the peculiar morphology of the cells. Any mutation or insult lowering the mitochondrial QC capacity is therefore predicted to affect neurons preferentially. Remarkably, this is exactly what human genetics has taught us in the last few years through the identification of genes involved in mitochondria QC as the cause of a large number of neurodegenerative diseases. Mutations in genes involved in organellar or intraorganellar levels of QC in mitochondria cause distinct neurodegenerative diseases mainly characterized by involvement of the peripheral nerves, the central motor neurons, cerebellar neurons and/or the optic nerve (Table I). Different forms of peripheral neuropathies are caused by mutations in mitofusin 2 (MFN2; Charcot-Marie-Tooth disease type 2A) (Zuchner et al, 2006), one of two dynamin-like GTPases mediating mitochondrial outer membrane (OM) fusion, and in GDAP1 (ganglioside-induced differentiation-associated protein 1), a mitochondrial OM protein whose function has been linked to the cellular glutathione metabolism and which is required for efficient fission (Niemann et al, 2005; Noack et al, 2011). Mutations in the dynamin-like GTPase OPA1 (optic atrophy 1) mediating mitochondrial inner membrane fusion and cristae organization are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells (Alexander et al, 2000; Delettre et al, 2000; Lenaers et al, 2009). Some familial forms of Parkinson's disease (PD) are caused by mutations in the E3 ubiquitin ligase Parkin and the PTEN-induced kinase PINK1 (Kitada et al, 1998; Valente et al, 2004), which are crucial regulators of mitophagy and mitochondrial turnover. Here, we focus on the link between mitochondrial proteases and neurodegeneration. We will first introduce neurodegenerative diseases that have been associated with specific components of intramitochondrial or organellar quality surveillance systems, before we discuss potential pathogenic mechanisms. Table 1. Neurodegenerative disorders associated with components of the mitochondrial QC system Name Location Process Disease Intramitochondrial quality control Paraplegin/SPG7 (m-AAA protease) IM, M Degradation of non-native proteins; protein processing Hereditary spastic paraplegia, AR (Casari et al, 1998) AFG3L2 (m-AAA protease) IM, M Degradation of non-assembled and damaged proteins; protein processing Spinocerebellar ataxia SCA28, AD (Di Bella et al, 2010) Spastic ataxia neuropathy syndrome, AR (Pierson et al, 2011) HTRA2/OMI IMS Degradation of damaged proteins; regulation of apoptosis Parkinson's disease (?) PARL IM Processing of PINK1, anti-apoptotic activity Parkinson's disease PreP M Degradation of presequences and oligopeptides, Aβ degradation Alzheimer's disease (?) HSP60 M Protein folding, protection against heat stress Hereditary spastic paraplegia, AD (Hansen et al, 2002); Mit-CHAP60, AR (Magen et al, 2008) Organellar quality control Mfn2 OM, MAM Fusion of OM, axonal transport of mitochondria, ER-mitochondria interaction Charcot-Marie Tooth diseases 2A, AD (Zuchner et al, 2006) OPA1 IM, IMS Fusion of IM, cristae morphogenesis, mtDNA stability Dominant optic atrophy, AD (Alexander et al, 2000; Delettre et al, 2000) GDAP1 IM Mitochondrial fission Charcot-Marie-Tooth disease 4A, AD, AR (Baxter et al, 2002) Parkin Cyt, OM Mitophagy Parkinson's disease (Kitada et al, 1998) PINK1 IM, OM Mitophagy Parkinson's disease (Valente et al, 2004) AD, autosomal dominant; AR, autosomal recessive; IM, inner membrane; IMS, intermembrane space; M, matrix; MAM, mitochondria-associated membrane; OM, outer membrane. Genes unambiguously identified in neurodegenerative diseases are referenced. Intramitochondrial QC and neurodegeneration Mutations in the m-AAA protease cause three neurological disorders The first evidence that dysfunctional mitochondrial proteases can cause neurodegeneration came in 1998 with the identification of disease-causing mutations in SPG7, which encodes a subunit of the hexameric, ATP-dependent m-AAA protease in the mitochondrial inner membrane (Casari et al, 1998). Loss-of-function mutations in the SPG7 gene were found in patients affected by an autosomal recessive form of hereditary spastic paraplegia (HSP), a progressive disorder clinically defined by weakness, spasticity (muscle rigidity) and loss of the vibratory sense of the lower limbs. HSP is genetically heterogeneous and caused by the selective retrograde degeneration of the longest motor and sensory axons of the central nervous system, the corticospinal tracts and the fasciculus gracilis (Reid and Rugarli, 2010). Corticospinal axons can reach the remarkable length of 1 m in adults, contain >99% of the cytoplasm of the cell, and heavily rely on transport of mitochondria and other cargos to synaptic terminals for their function. SPG7 is mutated in a small subset of familiar recessive HSP cases but in up to 11% of sporadic HSP patients (Brugman et al, 2008). Recently, one form of spinocerebellar ataxia, SCA28, was associated with heterozygous mutations in the molecular partner of paraplegin within the m-AAA protease, the homologous protein AFG3L2 (Cagnoli et al, 2010; Di Bella et al, 2010). Ataxia indicates lack of motor coordination and is associated with cerebellar dysfunction. SCA28 patients are affected by a slowly progressive gait and limb ataxia of juvenile onset, dysarthria (disturbance in articulation of speech), hyperreflexia at lower limbs (a sign of upper motor neuron dysfunction), nystagmus, ptosis and ophthalmoparesis. Different missense mutations were found in both familial and sporadic patients. Strikingly, mutations hit conserved residues in the peptidase domain. When the effect of these mutations was tested for their ability to rescue the loss of the yeast m-AAA protease they were found to be inactive variants (Di Bella et al, 2010). Therefore, while gain-of-function or dominant-negative effects cannot be formally excluded, evidence strongly suggest that these mutations lead to protein haploinsufficiency. A homozygous mutation in AFG3L2, substituting a conserved tyrosine at the beginning of the peptidase domain to a cysteine, has been also detected in two siblings of a consanguineous marriage who were affected by a severe early-onset syndrome characterized by severe spastic paraplegia, ataxia, ptosis, oculomotor apraxia, dystonic movements and stimulus-induced myoclonus (Pierson et al, 2011). Strikingly, this phenotype combines manifestations of both HSP and SCA28 along with clinical features of other mitochondrial diseases (such as ptosis, ophthalmoparesis and myoclonic epilepsy). Again, a yeast model system was employed to assess the pathogenicity of the identified mutation. In contrast to mutations involved in SCA28, this variant was found to retain some residual activity, but its assembly into m-AAA protease complexes was strongly impaired. Reduced levels of assembled m-AAA complexes were confirmed in fibroblasts from one of the patients (Pierson et al, 2011). One of the biggest puzzles in both neurodegenerative and mitochondrial diseases is the remarkable tissue specificity of the clinical phenotypes caused by the disruption of proteins that are often ubiquitously expressed and that perform conserved housekeeping functions. Combining biochemical, genetic and expression data, we start to decipher this conundrum for neurodegenerative diseases caused by mutations in subunits of the m-AAA protease (Figure 2). Paraplegin and AFG3L2 are highly homologous, evolutionary conserved proteins (54% protein sequence homology), containing two transmembrane domains, the AAA domain, and an M41 metallopeptidase domain (Gerdes et al, 2011). However, they differ in their ability to homo-oligomerize. While AFG3L2 forms homo-oligomeric assemblies or hetero-oligomeric complexes with paraplegin, the activity of paraplegin depends on its assembly with AFG3L2 into functional m-AAA proteases (Koppen et al, 2007). Both human isoenzymes are functionally conserved and can substitute for the orthologous yeast m-AAA protease, a hetero-oligomer of Yta10 and Yta12 subunits, which degrades misfolded inner membrane proteins and regulates mitochondrial translation (Leonhard et al, 2000; Nolden et al, 2005). The presence of different m-AAA isoenzymes, however, has important implications for understanding the pathogenesis of the associated human diseases. Mutations in SPG7 only affect the hetero-oligomeric m-AAA complex, while mutations in AFG3L2 perturb both isoforms. In view of the functional redundancy of m-AAA isoenzymes, the relative expression level of both subunits will determine the total residual amount of m-AAA proteases in a given patient, which will also be different if the patient carries a homozygous mutation (as in HSP or in the severe spastic-ataxia syndrome patients) or a heterozygous one (as in SCA28 patients). The expression levels of the two subunits indeed vary among murine tissues and within different regions of the brain. While Afg3l2 is ubiquitously expressed at high level in any neuronal cell type, Spg7 appears to be expressed at lower levels and specifically in certain neurons, such as pyramidal cells of the cerebral cortex (Martinelli et al, 2009). It is therefore plausible that different neurons might contain different amounts of homo-oligomeric versus hetero-oligomeric complexes and be differentially affected by mutations in AFG3L2 or SPG7. Moreover, it is conceivable that specific substrates might exist which can be handled preferentially by one type of complex, or that individual tissues or neuronal cell types might express specific substrates. In conclusion, dosage effects, combined with possible mishandling of critical substrates, could reconcile the different severity and pattern of neuronal degeneration observed in human patients. Figure 2.Possible pathogenic mechanisms of neurodegenerative disorders caused by mutations in m-AAA protease subunits. Mutations in the m-AAA protease subunit AFG3L2 impair the activity of both homo- and hetero-oligomeric m-AAA isoenzymes, while mutations in paraplegin (SPG7) affect only the hetero-oligomeric m-AAA protease. Accumulating misfolded polypeptides or deficiencies in mitochondrial biogenesis and dynamics may interfere with mitochondrial energy output and axonal trafficking of mitochondria. Download figure Download PowerPoint The analysis of mouse models for individual m-AAA protease subunits has largely supported this scenario. Paraplegin-deficient mice show a late-onset progressive distal axonopathy of long sensory and central motor axons, optic nerves and peripheral nerves (Ferreirinha et al, 2004). Heterozygous Afg3l2+/− animals exhibit late-onset cerebellar degeneration, while double Spg7−/− Afg3l2+/− animals show a striking acceleration of the phenotype of the two individual mouse models, demonstrating functional redundancy in vivo (Maltecca et al, 2009; Martinelli et al, 2009). Two different Afg3l2 models, a spontaneous mutant carrying a missense mutation in the ATPase domain and a knockout model generated by retroviral insertion in the gene, have instead a very severe developmental phenotype, and die as early as P15 (Duchen et al, 1983; Maltecca et al, 2008). These mice still bear residual complex activity since the mouse expresses Afg3l1, a highly homologous gene to Afg3l2 that in human has become a pseudogene (Kremmidiotis et al, 2001). Interestingly, these mice do not show a reduced number of neurons or abnormalities in neuronal migration or lamination, but a defect to develop and myelinate axons (Maltecca et al, 2009). Thus, the total cellular capacity of mitochondrial QC appears to become limited when neurons elongate axons and form synaptic contacts. PD and mitochondrial HTRA2 PD is one of the most common neurodegenerative diseases in the aging population. It is characterized by the clinical triad of rigidity, bradikinesia and tremor, and by the neuropathological loss of dopaminergic neurons (DNs) in the substantia nigra with typical intracytoplasmatic ubiquitin- and α-synuclein-positive inclusions, the Lewy bodies. A strong link between mitochondrial dysfunction and PD is supported by the findings that neurotoxins affecting respiratory complex I induce specific death of DNs, and by the discovery that a number of causative genes in familial forms of PD encode mitochondrial proteins. Remarkably, emerging pathogenic pathways in PD are related to an impaired mitochondrial QC. The mitochondrial peptidase HTRA2/OMI, which is localized to the mitochondrial intermembrane space and homologous to the bacterial HtrA stress responsive genes, DegP and DegS (Vande Walle et al, 2008; Clausen et al, 2011), plays a critical role in protecting neurons against degeneration and has been associated with PD. Both a spontaneous mutation and a targeted deletion in the murine Htra2 gene were shown to cause a progressive neurodegenerative phenotype, characterized by abnormal gait, ataxia, repetitive movements and akinesia, owing to loss of neurons in the striatum (Jones et al, 2003; Martins et al, 2004). While its role in neuronal survival is well established, the implication of HTRA2 in the pathogenesis of PD remains controversial. HTRA2 has been found to be a component of α-synuclein-containing inclusions in brains of individuals with PD, dementia with Lewy bodies and multiple-system atrophy (Strauss et al, 2005; Kawamoto et al, 2008). Furthermore, some groups have reported the association of polymorphisms and mutations in HTRA2 with sporadic PD cases (Strauss et al, 2005; Bogaerts et al, 2008). However, these results have not been reproduced in large-scale studies on PD patients (Ross et al, 2008; Simon-Sanchez and Singleton, 2008; Kruger et al, 2011). Finally, the function of HTRA2 has been linked to PINK1. HTRA2 was found to be phosphorylated by the p38 pathway in a PINK1-dependent manner, and phosphorylated HTRA2 to be increased in the brain of sporadic PD patients and decreased in PINK1 mutated patients (Plun-Favreau et al, 2007). However, studies in D. melanogaster have come to different and conflicting conclusions (Whitworth et al, 2008; Yun et al, 2008; Tain et al, 2009). Taken together, the role of HTRA2 for the pathogenesis of PD has to be taken with caution and some findings need to be revisited critically. Nevertheless, the central role of PINK1 and parkin, both associated with juvenile forms of PD (Kitada et al, 1998; Valente et al, 2004), in mitophagy suggests that impaired mitochondrial QC is of pathogenic relevance in PD as will be discussed in more detail below. Alzheimer's disease and the Aβ-degrading mitochondrial oligopeptidase PreP Oligopeptidases form another class of mitochondrial proteases, whose functions have been linked to neurodegeneration. The proteolytic breakdown of misfolded proteins by various ATP-dependent proteases or the maturation of mitochondrial preproteins upon import into mitochondria results in the generation of peptides, which are further degraded to amino acids by oligopeptidases. The matrix-localized oligopeptidase PreP was originally identified in plant mitochondria by its ability to degrade mitochondrial presequences (Stahl et al, 2002). The crystal structure of this conserved peptidase with homologues identified in yeast and human mitochondria revealed a large proteolytic cavity whose accessibility is regulated by substrate binding (Johnson et al, 2006). The substrate specificity appears to be degenerate (Moberg et al, 2003; Kambacheld et al, 2005). Unexpectedly, studies on human brain mitochondria have demonstrated that PreP is the main peptidase degrading the amyloid β (Aβ) peptide associated with Alzheimer's disease (AD) (Falkevall et al, 2006). AD is a progressive neurodegenerative disorder characterized by the accumulation of intracellular neurofibrillary tangles and extracellular plaques of Aβ peptides in the brain. A dysfunction of mitochondria is among the earliest effects observed in AD brains but its causative role for disease pathogenesis is presently unclear, mainly as AD-causing mutations in mitochondrial proteins have not been identified. Interestingly, Aβ peptides were detected in post-mortem brain mitochondria of AD patients (Lustbader et al, 2004), raising the possibility of a role of mitochondrial Aβ for disease progression. Current models for the toxicity of Aβ propose that Aβ" @default.
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• W1926695909 date "2012-02-21" @default.
• W1926695909 modified "2023-10-18" @default.
• W1926695909 title "Mitochondrial quality control: a matter of life and death for neurons" @default.
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