Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences
2012; Springer Nature; Volume: 31; Issue: 14 Linguagem: Inglês
10.1038/emboj.2012.170
ISSN1460-2075
AutoresNicole Exner, A. Kathrin Lutz, Christian Haass, Konstanze F. Winklhofer,
Tópico(s)Neurological diseases and metabolism
ResumoReview26 June 2012free access Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences Nicole Exner Nicole Exner Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany Search for more papers by this author Anne Kathrin Lutz Anne Kathrin Lutz Munich, Germany Munich, Germany Search for more papers by this author Christian Haass Christian Haass Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany Munich, Germany Search for more papers by this author Konstanze F Winklhofer Corresponding Author Konstanze F Winklhofer Munich, Germany Munich, Germany Search for more papers by this author Nicole Exner Nicole Exner Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany Search for more papers by this author Anne Kathrin Lutz Anne Kathrin Lutz Munich, Germany Munich, Germany Search for more papers by this author Christian Haass Christian Haass Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany Munich, Germany Search for more papers by this author Konstanze F Winklhofer Corresponding Author Konstanze F Winklhofer Munich, Germany Munich, Germany Search for more papers by this author Author Information Nicole Exner1, Anne Kathrin Lutz2,3, Christian Haass1,3 and Konstanze F Winklhofer 2,3 1Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany 2Munich, Germany 3Munich, Germany *Corresponding author. Neurobiochemistry, German Center for Neurodegenerative Diseases (DZNE) Munich, Schillerstrasse 44, Munich 80336, Germany. Tel.:+49 89 2180 75483; Fax:+49 89 2180 75415; E-mail: [email protected] The EMBO Journal (2012)31:3038-3062https://doi.org/10.1038/emboj.2012.170 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites. Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction has long been implicated in the etiopathogenesis of Parkinson's disease (PD), based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Studies on the function and dysfunction of these genes revealed that various aspects of mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control. Introduction Parkinson's disease (PD) is a heterogeneous neurodegenerative disease entity typically diagnosed by its cardinal motor symptoms, including bradykinesia, hypokinesia, rigidity, resting tremor, and postural instability, which are subsumed under the syndrome of parkinsonism. The motor manifestations are attributable to the degeneration of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNc), resulting in dopamine depletion and derangements of neuronal circuits in the basal ganglia target regions of these neurons. Another pathological hallmark of PD is the presence of α-synuclein-containing deposits in neuronal perikarya (Lewy bodies) and processes (Lewy neurites). The role of Lewy bodies in the pathogenic process is discussed controversially. Parkinsonism can occur in the absence of Lewy bodies, for instance in some cases of familial PD or in drug-induced parkinsonism (Davis et al, 1979; Langston et al, 1999; Nuytemans et al, 2010). On the other hand, Lewy body pathology is sometimes found at autopsy in individuals without reported symptoms of parkinsonism (Jellinger, 2009; Adler et al, 2010). The manifestation of non-motor symptoms, some of which even precede the motor symptoms, reflect the fact that the neurodegenerative process is not limited to the SNc but has a much wider impact. Non-motor symptoms, such as autonomic dysfunction, sleep abnormalities, depression, and dementia, can contribute considerably to disability, as they usually are not responsive to dopamine replacement therapy. The etiopathogenesis of sporadic PD, the most common form of parkinsonism, is complex with variable contributions of genetic susceptibility and environmental factors (Figure 1). Ageing is one of the most important risk factors for sporadic PD. Given the demographic trend towards an aged population, the prevalence of PD and thus its socioeconomic burden will increase dramatically in the next decades. Over the last 15 years enormous effort has been taken to unravel the role of genetics in PD pathogenesis. Linkage analyses discovered six genes associated with Mendelian forms of parkinsonism, and genome-wide association studies identified susceptibility genes contributing to the risk for sporadic PD. Strikingly, there is an overlap between Mendelian genes and risk genes in the case of α-synuclein and leucine-rich repeat kinase 2 (LRRK2), blurring the traditional boundaries between familial and sporadic PD. The identification of genes associated with parkinsonism has had a major impact on PD research, allowing to dissect molecular pathways implicated in the pathogenesis. From genetic cellular and animal models, it emerged that mitochondrial alterations, oxidative stress, and impaired clearance of misfolded proteins and damaged organelles by proteasomal and lysosomal degradation pathways contribute to the disease process (reviewed in Dawson et al, 2010; Corti et al, 2011; Martin et al, 2011; and Shulman et al, 2011). Moreover, there is increasing evidence that sporadic and familial variants of PD share some common pathways that converge at mitochondria (reviewed in Abou-Sleiman et al, 2006; Lin and Beal, 2006; Mandemakers et al, 2007; Bogaerts et al, 2008; Henchcliffe and Beal, 2008; Schapira, 2008; Vila et al, 2008; Van Laar and Berman, 2009; Bueler, 2010; Burbulla et al, 2010; Winklhofer and Haass, 2010; and Schon and Przedborski, 2011). In the following, we will review our current knowledge on the role of mitochondria in PD pathogenesis and how these insights have changed our conceptional thinking and may eventually be translated into novel neuroprotective approaches. Figure 1.Aetiology of Parkinson's disease (PD) and possible links to mitochondrial integrity. Familial PD is caused by mutations in genes identified by linkage analyses that are inherited in an autosomal recessive or dominant manner. Sporadic PD is considered to be a complex neurodegenerative disease entity with both genetic susceptibility and environmental factors contributing to the etiopathogenesis. Recent genome-wide association studies have identified susceptibility loci, which in two cases (α-synuclein and LRRK2) overlap with classical PD genes, linking the aetiology of familial parkinsonism with that of sporadic PD. Both genetic and environmental factors influence various mitochondrial aspects, such as bioenergetics, dynamics, transport, and quality control. Download figure Download PowerPoint Mitochondrial dysfunction in sporadic PD The role of complex I deficiency and mitochondrial DNA mutations The first link between parkinsonism and mitochondria became evident in the early 1980s, when it was discovered that a neurotoxin causing a parkinsonian syndrome inhibits mitochondrial respiration. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a contaminant of an illicit opioid preparation which was used intravenously by drug addicts, can cross the blood–brain barrier and is taken up by DA neurons via the dopamine transporter after oxidation to MPP+ (Langston et al, 1983; Nicklas et al, 1985). Within DA neurons, MPP+ accumulates in mitochondria and inhibits complex I (NADH ubiquinone oxidoreductase) of the electron transport chain. Although MPTP-induced parkinsonism results from an acute toxic insult and therefore differs from the slow and progressive disease process in sporadic PD, the impact of MPTP has been far reaching. In particular, MPTP and other complex I inhibitors such as rotenone are still being used to model PD in animals and to evaluate therapeutic approaches (reviewed in Hirsch, 2007; Bezard and Przedborski, 2011; and Cannon and Greenamyre, 2011). Interestingly, consumption of fruit and herbal teas from plants of the Annonceae family, containing the complex I inhibitor annonacin, has been linked to the high frequency of atypical parkinsonism in Guadeloupe (Caparros-Lefebvre and Elbaz, 1999; Lannuzel et al, 2003; Champy et al, 2004), further substantiating a causal role of mitochondrial dysfunction in the pathogenesis of at least some parkinsonian syndromes. In support of a direct or indirect role of complex I, the activity of complex I has been reported to be reduced (in the range of 30%) in the SNc and frontal cortex of PD patients at autopsy (Schapira et al, 1989; Parker et al, 2008). In mitochondrial preparations from PD frontal cortex samples, complex I subunits derived from both mitochondrial and nuclear genomes were found to be oxidatively damaged, reflected by an increase in protein carbonyls (Keeney et al, 2006). This study also reported that the levels of an 8-kDa subunit of complex I were reduced by 33% in PD frontal cortex, suggesting that oxidative damage may cause misassembly or reduced stability of complex I subunits. Remarkably, in about 25% of PD patients analysed complex I activities were found to be reduced also in platelets (reviewed in Schapira, 2008). This finding may indicate a systemic complex I defect in a subfraction of PD patients due to genetic and/or environmental causes. In a mouse model of mild complex I deficiency induced by the dopamine neuron-specific loss of the Ndufs4 subunit, increased striatal dopamine turnover rates and decreased dopamine release from striatal axon terminals have been observed (Sterky et al, 2012). These alterations in striatal dopamine homeostasis may be caused by a reduced vesicular uptake of dopamine due to ATP deficiency followed by enhanced cytosolic dopamine metabolism, suggesting that impaired dopamine release may be an early consequence of mitochondrial impairment (Choi et al, 2011; Sterky et al, 2012). Mitochondrial oxidative phosphorylation depends on both mitochondrial and nuclear DNA-encoded proteins. Mitochondrial DNA (mtDNA) encodes 13 proteins that are all subunits of respiratory chain complexes, 22 tRNAs, and 2 rRNAs. Mutations in mtDNA can be either inherited maternally or acquired and typically cause variable phenotypes in cells with high energy demands, such as neurons and muscle cells. Mouse models with defects in genes essential for the maintenance of mtDNA support the notion that alterations in the mitochondrial genome cause respiratory chain deficiencies and phenotypes associated with ageing and age-related diseases (reviewed in Reeve et al, 2008; Larsson, 2010; and Park and Larsson, 2011). Transgenic mice expressing a proofreading-deficient version of the mtDNA polymerase γ (POLG) accumulate mtDNA mutations and display features of premature ageing (Trifunovic et al, 2004; Kujoth et al, 2005). Notably, cosegregation of parkinsonism with mutations in the human POLG1 gene has been reported in several families (reviewed in Orsucci et al, 2011). In support of a causative role of mitochondrial dysfunction in PD, mice with a DA neuron-specific deletion of the mitochondrial transcription factor TFAM, which is essential for mitochondrial transcription and maintenance of mtDNA, develop a parkinsonian phenotype reproducing key features of PD: adult onset, progressive impairment of motor functions responsive to L-DOPA therapy, and loss of midbrain DA neurons (Ekstrand et al, 2007). Similarly, expression of mitochondrially targeted PstI endonuclease in DA neurons, which induces double-strand breaks in mtDNA, causes progressive neuronal degeneration and striatal dopamine depletion (Pickrell et al, 2011). An age-dependent increase in mtDNA deletions has been found in individual DA neurons dissected from the SNc of post mortem human brain (Bender et al, 2006; Kraytsberg et al, 2006). Neurons harbouring >60% of mtDNA molecules with deletions showed a significant decrease in cytochrome c oxidase, three catalytic subunits of which are encoded by mtDNA. Different types of mtDNA deletions were found in the same individual, but each neuron contained only a single mtDNA mutation, indicating that the mutation was acquired and clonally expanded. In comparison with age-matched controls, the amount of mtDNA mutations was slightly higher in DA neurons from PD patients (Bender et al, 2006). Moreover, SNc neurons seem to be particularly vulnerable to mtDNA mutations, since hippocampal neurons or pyramidal cortical neurons of aged individuals did not contain high levels of mtDNA mutations. There is currently no strong evidence that mtDNA mutations are a major primary cause of PD. However, it seems quite plausible that mtDNA mutations accumulate in the course of the disease as a consequence of an increase in cellular stress and mitochondrial replication errors along with a decrease in the fidelity of quality control systems. Once the mtDNA mutations surpass a critical threshold, the resulting respiratory deficiency may contribute to neuronal degeneration and cell death. Of note, complex I is particularly vulnerable to mtDNA damage, since seven of its subunits are encoded by mtDNA. Mitochondrial dysfunction and oxidative stress According to a widespread concept, inhibition of complex I decreases mitochondrial ATP production and increases the formation of reactive oxygen species (ROS), which damage mtDNA, components of the respiratory chain and other mitochondrial factors, thereby triggering a vicious circle between mitochondrial impairment and oxidative stress (reviewed in Abou-Sleiman et al, 2006; Lin and Beal, 2006; and Henchcliffe and Beal, 2008). This model has been particularly popular to explain the increased vulnerability of SNc DA neurons, since this neuronal population is characterized by a high oxidative burden and a low anti-oxidant capacity. Mitochondria can be both a source and a target of ROS (reviewed in Starkov, 2008 and Murphy, 2009). However, an obligatory link between mitochondrial dysfunction and increased ROS production has been questioned based on weak experimental support for such a scenario in vivo (reviewed in Fukui and Moraes, 2008; Gems and Doonan, 2009; and Park and Larsson, 2011). For example, rotenone toxicity has been reported to be caused by spare respiratory capacity rather than oxidative stress. In primary neurons, rotenone does increase the formation of mitochondrial superoxide, however, trapping superoxide fails to reduce rotenone toxicity (Yadava and Nicholls, 2007). In addition, various mouse models with severe respiratory chain deficiency display increased apoptotic cell death but not increased ROS formation or oxidative stress (Wang et al, 2001; Kujoth et al, 2005; Trifunovic et al, 2005; Kruse et al, 2008). Moreover, ROS are not always harmful agents, they also act as important signal transducers in a variety of biological processes. Mitochondrial effects of genes associated with PD Parkin: a versatile neuroprotective E3 ubiquitin ligase The parkin gene has been identified in 1998 as a causative gene for autosomal recessive parkinsonism (Kitada et al, 1998). More than 100 pathogenic parkin mutations have been reported, accounting for the majority of autosomal recessive parkinsonism. The parkin gene encodes a cytosolic 465 amino-acid protein with a ubiquitin-like (UBL) domain at the N-terminus and an RBR (RING-between-RING) domain close to the C-terminus. The RBR domain is composed of two RING fingers that flank an in-between RING (IBR) domain and coordinates six zinc ions. An additional RING finger domain (RING0) has been identified between the UBL and RBR motifs, which contributes to the binding of zinc ions (Hristova et al, 2009). Coordination of zinc ions (eight Zn2+ in total) is essential for parkin to adopt and maintain its correct three-dimensional structure, consistent with the observation that pathogenic mutations within the zinc-binding motifs are inactivated by misfolding (Cookson et al, 2003; Gu et al, 2003; Sriram et al, 2005; Wang et al, 2005b, 2007). Moreover, the cysteine-rich RBR domain renders parkin vulnerable to inactivation by severe oxidative stress (Winklhofer et al, 2003; LaVoie et al, 2007; Wong et al, 2007; Schlehe et al, 2008). Oxidatively modified, misfolded parkin has indeed been found in the brains of PD patients, suggesting that inactivation of parkin may also play a role in sporadic PD (Pawlyk et al, 2003; Chung et al, 2004; Yao et al, 2004; LaVoie et al, 2005; Wang et al, 2005a). In support of this notion, the c-Abl tyrosine kinase has been reported to be activated in DA neurons of sporadic PD patients, leading to the phosphorylation and inactivation of parkin (Ko et al, 2010; Imam et al, 2011). The presence of the RBR domain suggested that parkin acts as an E3 ubiquitin ligase, mediating the covalent attachment of ubiquitin moieties to substrate proteins (Shimura et al, 2000; Zhang et al, 2000). Considerable evidence has been accumulated indicating that parkin can catalyse various modes of ubiquitination, including poly-ubiquitination with different lysine linkages or mono-ubiquitination. The linkage type determines the fate of the ubiquitinated protein; ubiquitin chain linkage via Lys48 typically targets substrates for proteasomal degradation, whereas linkage involving other lysine residues and mono-ubiquitination or multiple mono-ubiquitination are implicated in numerous regulatory processes, such as signal transduction, trafficking, DNA damage response, DNA repair, and autophagy (reviewed in Komander, 2009; Ikeda et al, 2010; and Behrends and Harper, 2011). There are two major classes of E3 ubiquitin ligases: HECT ligases transiently accept ubiquitin from an E2 conjugating enzyme at a cysteine residue within the HECT domain to form a thioester, whereas RING-type ligases act as bridging proteins that bring the ubiquitin-charged E2 in close proximity to the substrate, but are not ubiquitinated themselves (reviewed in Deshaies and Joazeiro, 2009). It was recently shown that parkin functions as an RING/HECT hybrid: RING1 binds to a ubiquitin-charged E2 conjugating enzyme, which transfers ubiquitin to a conserved cysteine residue in RING2, thereby forming a thioester between parkin and ubiquitin (Wenzel et al, 2011). Ubiquitin is then discharged to a lysine residue of the substrate protein. So far, this mechanism has been demonstrated in vitro with recombinant parkin and auto-ubiquitination of parkin as a surrogate substrate, but undoubtedly, these findings have a major impact on our understanding of the substrate specificity of RBR E3 ligases. To date, about 30 putative parkin substrates have been reported and both degradative and non-degradative ubiquitination were attributed to parkin (reviewed in Dawson and Dawson, 2010). These substrates do not fit into a common pathway that could unravel the function of parkin. However, from a plethora of studies in cellular and animal models it emerged that parkin has a remarkably wide protective capacity. The increased expression of parkin both in vitro and in vivo protects against cell death in various stress paradigms, such as mitochondrial stress, endoplasmic reticulum (ER) stress, excitotoxicity, and proteotoxic stress (reviewed in Moore, 2006 and Pilsl and Winklhofer, 2012). Vice versa, parkin-deficient cells are characterized by an increased vulnerability to stress-induced cell death. Surprisingly, the sensitivity of parkin knockout (KO) mice to neurotoxins, such as MPTP or 6-OHDA seems not to be increased; nigral degeneration in parkin KO mice has only been reported after inflammatory stimulation by lipopolysaccaride (Perez et al, 2005; Thomas et al, 2007; Frank-Cannon et al, 2008). In line with parkin playing a role in the cellular stress response, parkin gene expression is considerably upregulated under cellular stress. ATF4 and p53 have been shown to increase parkin expression, whereas c-Jun and N-myc act as transcriptional repressors of parkin (West et al, 2004; Bouman et al, 2011; Zhang et al, 2011). Several viability pathways were reported to be influenced by parkin, including JNK, PI3K, and NF-κB signalling, p53 transcriptional activity, or Bax activation (Cha et al, 2005; Yang et al, 2005; Fallon et al, 2006; Henn et al, 2007; Hasegawa et al, 2008; da Costa et al, 2009; Sha et al, 2010; Johnson et al, 2012). Parkin has recently been shown to induce the proteasomal degradation of PARIS (parkin-interacting substrate), which acts as a transcriptional repressor of PGC-1α (peroxisome proliferator-activated receptor gamma-co-activator 1-alpha) (Shin et al, 2011). PGC-1α stimulates mitochondrial biogenesis as a co-activator of various transcription factors, such as NRF (nuclear respiratory factor)-1 and -2 (reviewed in Scarpulla, 2011). Thus, loss of parkin function suppresses mitochondrial biogenesis through an accumulation of PARIS. This study not only provided an important link between the protective activity of parkin and mitochondria but also implicated a transcriptional program in mediating the effects of parkin. Moreover, by generating conditional parkin KO mice Dawson and coworkers could show for the first time that loss of parkin function in adult mice leads to a progressive degeneration of DA neurons which can be suppressed by silencing PARIS expression (Shin et al, 2011). This finding supports the notion that developmental compensation accounts for the absence of major phenotypic alterations in germline parkin KO mice. Parkin at the interface of neurodegeneration and cancer In an attempt to characterize FRA6E, one of the most active common fragile sites in the human genome located at chromosome 6q25-q27, the parkin genomic structure was found to span a large region of FRA6E (Cesari et al, 2003; Denison et al, 2003a). Common fragile sites are specific loci that are susceptible to chromosomal breaks and rearrangements and seem to play a role in oncogenesis. Studies to detect genomic copy number variations in human ovarian and breast carcinomas identified a common minimal region of loss located within the parkin gene. Indeed, decreased or absent parkin expression was observed in various malignancies (Cesari et al, 2003; Denison et al, 2003a, 2003b; Picchio et al, 2004; Wang et al, 2004; Agirre et al, 2006; Fujiwara et al, 2008; Ikeuchi et al, 2009; Poulogiannis et al, 2010; Veeriah et al, 2010; Mehdi et al, 2011). Several studies have now provided considerable evidence that parkin might be a bona fide tumour suppressor gene (TSG). Heterozygous deletion of parkin accelerated the development of intestinal adenoma in mice expressing mutant APC, a regulator of Wnt signalling (Poulogiannis et al, 2010). Upon γ-irradiation parkin KO mice developed lymphomas in the spleen with a shorter tumour latency compared with wild-type mice (Zhang et al, 2011). In one line of parkin KO mice lacking exon 3, enhanced hepatocyte proliferation and development of hepatic tumours has been observed (Fujiwara et al, 2008). Ectopic expression of parkin in parkin-deficient tumour cells lines (glioma cells or lung cancer cells) resulted in reduced tumour growth after injection of these cells as xenografts into nude mice (Picchio et al, 2004; Veeriah et al, 2010). Some studies reported that parkin overexpression inhibits cell proliferation, albeit this is not a consistent finding (Picchio et al, 2004; Poulogiannis et al, 2010; Tay et al, 2010; Veeriah et al, 2010). The mechanism underlying the tumour suppressor activity of parkin is not well understood. A previous study identified cyclin E as a substrate of parkin for ubiquitination and proteasomal degradation in neuronal cells (Staropoli et al, 2003); therefore, it is tempting to speculate that a decrease in parkin expression results in an accumulation of cyclin E, a cell-cycle regulator required for the transition from G1 to S phase. Increased levels of cyclin E have been observed in some but not all parkin-deficient primary tumours and cancer cell lines (Ikeuchi et al, 2009; Tay et al, 2010; Veeriah et al, 2010; Yeo et al, 2012). Based on the effect of parkin on mitochondrial bioenergetics as reviewed further below, it is also conceivable that parkin exerts its tumour suppressor activity via influencing tumour metabolism. Evidence for such a scenario was recently provided by Feng and coworkers (Zhang et al, 2011). A hallmark of tumour cells is the switch from mitochondrial energy production to aerobic glycolysis, which is known as the Warburg effect (reviewed in Vander Heiden et al, 2009 and Cairns et al, 2011). To compensate for the lower efficiency of ATP production by glycolysis compared with mitochondrial respiration, tumour cells increase glucose uptake and utilization. An important role in regulating energy metabolism plays the TSG p53, a transcription factor that promotes mitochondrial respiration and reduces glycolysis via transcription of specific target genes. Parkin was recently identified as a p53 target gene, which can mediate effects of p53 on energy metabolism and antioxidant defense (Zhang et al, 2011). Parkin deficiency activates glycolysis and reduces mitochondrial respiration in human lung cancer cells and mouse embryonic fibroblasts, thereby contributing to the Warburg effect. Remarkably, parkin can also affect lipid metabolism by regulating fatty acid uptake. In wild-type mice, parkin expression is robustly upregulated upon exposure to a high fat and cholesterol diet (HFD), inducing the stabilization of the fatty acid transporter CD36, whereas parkin KO mice are resistant to weight gain and hepatic insulin resistance under HFD feeding (Kim et al, 2011). Whether germline pathogenic mutations in the parkin gene can increase the risk for cancer is difficult to assess given that parkin-linked parkinsonism is rare and a large number of cases would be required for a statistically robust epidemiological study (reviewed in Plun-Favreau et al, 2010 and Devine et al, 2011). PINK1: a mitochondrial kinase of complex regulation and processing The PINK1 (PTEN-induced putative kinase 1) gene was linked to autosomal recessive early onset PD in 2004 (Valente et al, 2004). It encodes a ubiquitously expressed 581 amino-acid protein with an N-terminal mitochondrial targeting sequence (MTS), a transmembrane domain and a highly conserved serine/threonine kinase domain with homology to the Ca2+/calmodulin family. About 30 pathogenic PINK1 mutations have been identified, among them missense, non-sense, or frameshift mutations, deletions or genomic rearrangements (reviewed in Deas et al, 2009; Nuytemans et al, 2010; and Corti et al, 2011). Most PINK1 mutations have been described to impair its kinase activity or reduce the stability of the protein, in line with a loss of function mechanism. The subcellular localization of PINK1 is still debated. PINK1 has been found at the outer and inner mitochondrial membrane and in the cytosol (Silvestri et al, 2005; Muqit et al, 2006; Haque et al, 2008; Lin and Kang, 2008; Weihofen et al, 2009; Jin et al, 2010; Narendra et al, 2010b; Murata et al, 2011; Shi et al, 2011). From recent research, a complex mechanism of PINK1 targeting and processing has emerged that could provide an explanation for the different observations regarding PINK1 localization. PINK1 seems to be imported via the TOM/TIM23 complexes at the outer/inner mitochondrial membrane in a membrane potential-dependent manner for cleaving off its MTS by the mitochondrial processing protease (Greene et al, 2012). PINK1 exposing its kinase domain to the intermembrane space could then be released from the transport pore by lateral diffusion to be further processed by a protease giving rise to a PINK1 fragment, which is subsequently degraded by an MG132-sensitive protease, possibly in the cytoplasm. How this retrotranslocation is mediated, is not known. It has been hypothesized that proteolytic cleavage of a PINK1 import intermediate still associated with the TOM complex leads to a C-terminal PINK1 fragment that reaches the cytoplasm by reverse translocation (Meissner et al, 2011). PARL (presenilin-associated rhomboid like protease) has recently been identified as a protease promoting PINK1 cleavage under basal conditions to keep mitochondrial PINK1 levels low (Whitworth et al, 2008; Jin et al, 2010; Deas et al, 2011; Meissner et al, 2011; Shi et al, 2011). When the mitochondrial membrane potential is dissipated, PINK1 mitochondrial import and processing by PARL is inhibited, leading to the integration of PINK1 into the outer mitochondrial membrane, which is a prerequisite to recruit parkin for the induction of mitophagy (Jin et al, 2010; Matsuda et al, 2010; Narendra et al, 2010b; Meissner et al, 2011) (see below). In depolarized mitochondria, endogenous PINK1 is associated with the TOM complex, which may allow rapid reimport of
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