Short Mitochondrial ARF Triggers Parkin/PINK1-dependent Mitophagy

Parkinson disease (PD) is a complex neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Multiple genes have been associated with PD, including Parkin and PINK1. Recent studies have established that the Parkin and PINK1 proteins function in a common mitochondrial quality control pathway, whereby disruption of the mitochondrial membrane potential leads to PINK1 stabilization at the mitochondrial outer surface. PINK1 accumulation leads to Parkin recruitment from the cytosol, which in turn promotes the degradation of the damaged mitochondria by autophagy (mitophagy). Most studies characterizing PINK1/Parkin mitophagy have relied on high concentrations of chemical uncouplers to trigger mitochondrial depolarization, a stimulus that has been difficult to adapt to neuronal systems and one unlikely to faithfully model the mitochondrial damage that occurs in PD. Here, we report that the short mitochondrial isoform of ARF (smARF), previously identified as an alternate translation product of the tumor suppressor p19ARF, depolarizes mitochondria and promotes mitophagy in a Parkin/PINK1-dependent manner, both in cell lines and in neurons. The work positions smARF upstream of PINK1 and Parkin and demonstrates that mitophagy can be triggered by intrinsic signaling cascades.     

Phosphorylation of Mitochondrial Polyubiquitin by PINK1 Promotes Parkin Mitochondrial Tethering

The kinase PINK1 and the E3 ubiquitin (Ub) ligase Parkin participate in mitochondrial quality control. The phosphorylation of Ser65 in Parkin''s ubiquitin-like (UBl) domain by PINK1 stimulates Parkin activation and translocation to damaged mitochondria, which induces mitophagy generating polyUb chain. However, Parkin Ser65 phosphorylation is insufficient for Parkin mitochondrial translocation. Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. The expression of Tom70^MTS-4xUb SE, which mimics phospho-Ser65 polyUb chains on the mitochondria, activated Parkin E3 activity and its mitochondrial translocation. An E3-dead form of Parkin translocated to mitochondria with reduced membrane potential in the presence of Tom70^MTS-4xUb SE, whereas non-phospho-polyUb mutant Tom70^MTS-4xUb SA abrogated Parkin translocation. Parkin binds to the phospho-polyUb chain through its RING1-In-Between-RING (IBR) domains, but its RING0-linker is also required for mitochondrial translocation. Moreover, the expression of Tom70^MTS-4xUb SE improved mitochondrial degeneration in PINK1-deficient, but not Parkin-deficient, Drosophila. Our study suggests that the phosphorylation of mitochondrial polyUb by PINK1 is implicated in both Parkin activation and mitochondrial translocation, predicting a chain reaction mechanism of mitochondrial phospho-polyUb production by which rapid translocation of Parkin is achieved.     

Mitochondrial chaperone DnaJA3 induces Drp1-dependent mitochondrial fragmentation

Mitochondrial morphology is dynamic and controlled by coordinated fusion and fission pathways. The role of mitochondrial chaperones in mitochondrial morphological changes and pathology is currently unclear. Here we report that altered levels of DnaJA3 (Tid1/mtHsp40) a mitochondrial member of the DnaJ protein family, and heat shock protein (Hsp) co-chaperone of matrix 70 kDa Hsp70 (mtHsp70/mortalin/HSPA9), induces mitochondrial fragmentation. Suppression of DnaJA3 induced mitochondrial fragmentation in HeLa cells. Elevated levels of DnaJA3 in normal Hs68 fibroblast cells and HeLa, SKN-SH, U87 and U251 cancer cell lines induces mitochondrial fragmentation. Mitochondrial fragmentation induction was not observed in HeLa cells when other DnaJA family members, or mitochondrial DnaJ protein HSC20, were ectopically expressed, indicating that the effects on mitochondrial morphology were specific to DnaJA3. We show that the DnaJ domain (amino acids 88-168) of DnaJA3 is sufficient for the induction of mitochondrial fragmentation. Furthermore, an H121Q point mutation of the DnaJ domain, which abrogates interaction and activation of mtHsp70 ATPase, eliminates fragmentation induced by DnaJA3. This suggests that DnaJA3 interaction with mtHsp70 may be critical in mitochondrial morphological changes. DnaJA3-induced mitochondrial fragmentation was dependent on fission factor dynamin-related protein 1 (Drp1). Ectopic expression of the mitofusins (Mfn1 and Mfn2), however, does not rescue DnaJA3-induced mitochondrial fragmentation. Lastly, elevated levels of DnaJA3 inducing mitochondrial fragmentation were associated with reduction in cell viability. Taken together, elevated DnaJA3 induces Drp1-depedendent mitochondrial fragmentation and decreased cell viability.     

Structural Mechanisms of Mitochondrial Quality Control Mediated by PINK1 and Parkin

Parkinson's disease (PD) is the second most common neurodegenerative disease and represents a looming public health crisis as the global population ages. While the etiology of the more common, idiopathic form of the disease remains unknown, the last ten years have seen a breakthrough in our understanding of the genetic forms related to two proteins that regulate a quality control system for the removal of damaged or non-functional mitochondria. Here, we review the structure of these proteins, PINK1, a protein kinase, and parkin, a ubiquitin ligase with an emphasis on the molecular mechanisms responsible for their recognition of dysfunctional mitochondria and control of the subsequent ubiquitination cascade. Recent atomic structures have revealed the basis of PINK1 substrate specificity and the conformational changes responsible for activation of PINK1 and parkin catalytic activity. Progress in understanding the molecular basis of mitochondrial quality control promises to open new avenues for therapeutic interventions in PD.     

Parkin blushed by PINK1

Mutations in the PTEN-induced putative kinase 1 (PINK1) are a common cause of autosomal recessive Parkinson's disease. In a recent issue of Nature, two independent reports by and show that loss of Drosophila PINK1 leads to defects in mitochondrial function resulting in male sterility, apoptotic muscle degeneration, and minor loss of dopamine neurons that is rescued by overexpression of the ubiquitin E3 ligase, parkin. Thus, PINK1 and parkin appear to function in a common pathway suggesting a convergence of the two genes most commonly associated with autosomal recessive PD.     

Drp1的调控对PINK1突变转基因果蝇的保护作用

帕金森病（PD）是以黑质致密部多巴胺神经元选择性减少和胞浆内路易小体的形成为特征的神经退行性疾病。研究发现,PTEN诱导激酶1(PINK1)基因突变导致家族性早发型帕金森病的发生。在转基因果蝇中,PINK1功能丢失导致间接飞行肌缺陷,线粒体结构、功能障碍,多巴胺神经元丢失。本研究在PINK1突变PD转基因果蝇中,进行发动蛋白相关蛋白1（Drp1）过表达和敲低,探索Drp1对PD转基因果蝇的保护作用及其可能机制。本研究选用MHC-Gal4/UAS系统的PD转基因果蝇模型,特异性启动PINK1B9基因于果蝇肌肉组织中表达;运用Drp1基因过表达和RNA干扰干预PINK1B9转基因果蝇,研究其对PD转基因果蝇的作用。结果显示,不论过表达Drp1还是Drp1敲低均可挽救PINK1突变转基因果蝇,降低翅膀异常率,改善飞行能力,恢复间接飞行肌排列,调节线粒体形态,提高ATP生成量,上调NDUFS3蛋白表达水平。本文结果提示,Drp1的调控挽救PINK1突变转基因果蝇与线粒体呼吸链有关。     

Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment

Mutations in phosphatase and tensin homologue-induced kinase 1 (PINK1) cause recessively inherited Parkinson's disease (PD), a neurodegenerative disorder linked to mitochondrial dysfunction. In healthy mitochondria, PINK1 is rapidly degraded in a process involving both mitochondrial proteases and the proteasome. However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. These results highlight a new role for MPP in PINK1 import and mitochondrial quality control via the PINK1–Parkin pathway.     

PINK1 points Parkin to mitochondria

For decades, it has been presumed that mitochondrial dysfunction, in the form of impaired complex I activity, may contribute to the cause of Parkinson disease (PD).¹ The discovery that several gene mutations cause familial forms of PD¹ has led to a renewed enthusiasm for the mitochondrial hypothesis of PD, but this time from a quite distinct and, perhaps, more realistic angle. Among these genes, those that code for PTEN-induced kinase-1 (PINK1)² and for the E3-ubiquitin ligase Parkin³ did attract major interest from mitochondriologists, in part, because both proteins interact with each other and apparently function, genetically, within the same molecular pathway to modulate mitochondrial dynamics in Drosophila.^4-6     

Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism

Mutations in Parkin or PINK1 are the most common cause of recessive familial parkinsonism. Recent studies suggest that PINK1 and Parkin form a mitochondria quality control pathway that identifies dysfunctional mitochondria, isolates them from the mitochondrial network, and promotes their degradation by autophagy. In this pathway the mitochondrial kinase PINK1 senses mitochondrial fidelity and recruits Parkin selectively to mitochondria that lose membrane potential. Parkin, an E3 ligase, subsequently ubiquitinates outer mitochondrial membrane proteins, notably the mitofusins and Miro, and induces autophagic elimination of the impaired organelles. Here we review the recent rapid progress in understanding the molecular mechanisms of PINK1- and Parkin-mediated mitophagy and the identification of Parkin substrates suggesting how mitochondrial fission and trafficking are involved. We also discuss how defects in mitophagy may be linked to Parkinson''s disease.Parkinson''s disease (PD) is the second most common neurodegenerative disorder and is characterized by cardinal motor symptoms: slowness of movement, rigidity, rest tremor, and postural instability (Ropper et al. 2009). Although these symptoms initially respond to drugs that modulate dopamine metabolism or surgeries that alter basal ganglia circuitry, the disease eventually progresses. With a modest exception (Olanow et al. 2009), no therapy has been shown to alter the disease course.The pathogenesis of sporadic Parkinson''s disease is likely complex involving altered metabolism of the protein α-synuclein, lysosomal dysfunction, and a dysregulated inflammatory response (reviewed in Shulman et al. 2011). Several lines of evidence also point to mitochondrial dysfunction as a central player in the pathogenesis of PD. Complex I dysfunction is associated with sporadic PD and is sufficient to induce parkinsonism (reviewed in Schapira 2008). The inhibitors of complex I, MPTP (Langston et al. 1983) and rotenone (Betarbet et al. 2000), replicate the symptoms of PD, and rotenone recapitulates key pathognomonic features of PD, such as the α-synuclein-rich inclusion bodies (Betarbet et al. 2000). The cause of mitochondrial dysfunction in sporadic PD is not entirely clear, but laser capture microdissection of substantia nigra neurons from patients with PD reveal a higher burden of mitochondrial DNA deletions relative to age-matched controls (Bender et al. 2006). That such deletions are sufficient to cause parkinsonism is suggested by the occurrence of parkinsonism in patients with rare mutations in their mtDNA replication machinery (e.g., the catalytic subunit of the mtDNA polymerase POLG [Luoma et al. 2004] or the mtDNA helicase Twinkle [Baloh et al. 2007]). The defective mtDNA replicative machinery generates high levels of mtDNA deletions throughout the body that are qualitatively similar to those observed in the substantia nigra in patients with sporadic PD (Reeve et al. 2008). Thus, mitochondrial dysfunction is both associated with sporadic PD and sufficient to cause the parkinsonian syndrome.As is discussed in this review, recent insights from certain genetic forms of PD—resulting from mutations in Parkin or PINK1—support the model that mitochondrial damage is a central driver of PD pathogenesis. Additionally, they provide a rationale for targeting mitochondrial quality control pathways in patients with PD.     

Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury

Objectives

Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson’s disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction.

Methods and Results

Over-expressing PINK1 in HL-1 cardiac cells reduced cell death following simulated IRI (29.2±5.2% PINK1 versus 49.0±2.4% control; N = 320 cells/group P<0.05), and delayed the onset of mitochondrial permeability transition pore (MPTP) opening (by 1.3 fold; P<0.05). Hearts excised from PINK1+/+, PINK1+/− and PINK1−/− mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK1−/− hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/− hearts (25.1±2.0% PINK1+/+, 38.9±3.4% PINK1+/− versus 51.5±4.3% PINK1−/− hearts; N>5 animals/group; P<0.05). Cardiomyocytes isolated from PINK1−/− hearts had a lower resting mitochondrial membrane potential, had inhibited mitochondrial respiration, generated more oxidative stress during simulated IRI, and underwent rigor contracture more rapidly in response to an uncoupler when compared to PINK1+/+ cells suggesting mitochondrial dysfunction in hearts deficient in PINK1.

Conclusions

We show that the loss of PINK1 increases the heart''s vulnerability to ischemia-reperfusion injury. This may be due, in part, to increased mitochondrial dysfunction. These findings implicate PINK1 as a novel target for cardioprotection.     

The Mitochondrial Fusion-Promoting Factor Mitofusin Is a Substrate of the PINK1/Parkin Pathway

Loss-of-function mutations in the PINK1 or parkin genes result in recessive heritable forms of parkinsonism. Genetic studies of Drosophila orthologs of PINK1 and parkin indicate that PINK1, a mitochondrially targeted serine/threonine kinase, acts upstream of Parkin, a cytosolic ubiquitin-protein ligase, to promote mitochondrial fragmentation, although the molecular mechanisms by which the PINK1/Parkin pathway promotes mitochondrial fragmentation are unknown. We tested the hypothesis that PINK1 and Parkin promote mitochondrial fragmentation by targeting core components of the mitochondrial morphogenesis machinery for ubiquitination. We report that the steady-state abundance of the mitochondrial fusion-promoting factor Mitofusin (dMfn) is inversely correlated with the activity of PINK1 and Parkin in Drosophila. We further report that dMfn is ubiquitinated in a PINK1- and Parkin-dependent fashion and that dMfn co-immunoprecipitates with Parkin. By contrast, perturbations of PINK1 or Parkin did not influence the steady-state abundance of the mitochondrial fission-promoting factor Drp1 or the mitochondrial fusion-promoting factor Opa1, or the subcellular distribution of Drp1. Our findings suggest that dMfn is a direct substrate of the PINK1/Parkin pathway and that the mitochondrial morphological alterations and tissue degeneration phenotypes that derive from mutations in PINK1 and parkin result at least in part from reduced ubiquitin-mediated turnover of dMfn.     

Parkin stabilizes PINK1 through direct interaction

Parkinson disease (PD) is the most common movement disorder and is characterized by dopaminergic dysfunction. The majority of PD cases are sporadic; however, the discovery of genes linked to rare familial forms of the disease has provided crucial insight into the molecular mechanisms of disease pathogenesis. Multiple genes mediating familial forms of Parkinson’s disease (PD) have been identified, such as parkin (PARK2) and phosphatase and tensin homologue deleted on chromosome ten (PTEN)-induced putative kinase 1: PINK1 (PARK6). Here, we showed that Parkin directly interacts with PINK1, but did not bind to pathogenic PINK1 mutants. Parkin, but not its pathogenic mutants, stabilizes PINK1 by interfering with its degradation via the ubiquitin-mediated proteasomal pathway. In addition, the interaction between Parkin and PINK1 resulted in reciprocal reduction of their solubility. Our results indicate that Parkin regulates PINK1 stabilization via direct interaction with PINK1, and operates through a common pathway with PINK1 in the pathogenesis of early-onset PD.     

Parkin功能丧失增强细胞自噬

Parkin(PARK2)基因的突变与家族性帕金森综合症的发生密切相关,其蛋白Parkin是细胞内的E3泛素连接酶。当线粒体受到损伤时,Parkin会募集到线粒体上,介导线粒体自噬,在生理条件下,Parkin及Parkin突变体是否会引起细胞自噬还不清楚。本文研究了病理性Parkin突变体对细胞自噬的影响。通过构建一系列Parkin功能缺失的突变体,并转染到HeLa以及ATG5-/-MEF细胞中,利用免疫荧光技术和Western-blot分析这些突变体对细胞自噬的影响。结果表明,Parkin突变体的表达促进细胞自噬的标志分子LC3由LC3-Ⅰ型变为LC3-Ⅱ型。突变体R275W在细胞内形成蛋白聚集体,并与LC3共定位。当细胞自噬的关键基因ATG5被敲除后,Parkin突变体引起的细胞自噬受到显著抑制。我们的初步结果提示Parkin突变体通过Atg5影响细胞自噬,并可能与帕金森症的发生有一定的相关性。     

Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1

The mitochondrial chaperone mortalin was implicated in Parkinson''s disease (PD) because of its reduced levels in the brains of PD patients and disease-associated rare genetic variants that failed to rescue impaired mitochondrial integrity in cellular knockdown models. To uncover the molecular mechanisms underlying mortalin-related neurodegeneration, we dissected the cellular surveillance mechanisms related to mitochondrial quality control, defined the effects of reduced mortalin function at the molecular and cellular levels and investigated the functional interaction of mortalin with Parkin and PINK1, two PD-related proteins involved in mitochondrial homeostasis. We found that reduced mortalin function leads to: (1) activation of the mitochondrial unfolded protein response (UPR(mt)), (2) increased susceptibility towards intramitochondrial proteolytic stress, (3) increased autophagic degradation of fragmented mitochondria and (4) reduced mitochondrial mass in human cells in vitro and ex vivo. These alterations caused increased vulnerability toward apoptotic cell death. Proteotoxic perturbations induced by either partial loss of mortalin or chemical induction were rescued by complementation with native mortalin, but not disease-associated mortalin variants, and were independent of the integrity of autophagic pathways. However, Parkin and PINK1 rescued loss of mortalin phenotypes via increased lysosomal-mediated mitochondrial clearance and required intact autophagic machinery. Our results on loss of mortalin function reveal a direct link between impaired mitochondrial proteostasis, UPR(mt) and PD and show that effective removal of dysfunctional mitochondria via either genetic (PINK1 and Parkin overexpression) or pharmacological intervention (rapamycin) may compensate mitochondrial phenotypes.     

PINK1 Is Dispensable for Mitochondrial Recruitment of Parkin and Activation of Mitophagy in Cardiac Myocytes

Myocyte function and survival relies on the maintenance of a healthy population of mitochondria. The PINK1/Parkin pathway plays an important role in clearing defective mitochondria via autophagy in cells. However, how the PINK1/Parkin pathway regulates mitochondrial quality control and whether it coordinates with other mitophagy pathways are still unclear. Therefore, the objective of this study was to investigate the effect of PINK1-deficiency on mitochondrial quality control in myocytes. Using PINK1-deficient (PINK1-/-) mice, we found that Parkin is recruited to damaged cardiac mitochondria in hearts after treatment with the mitochondrial uncoupler FCCP or after a myocardial infarction even in the absence of PINK1. Parkin recruitment to depolarized mitochondria correlates with increased ubiquitination of mitochondrial proteins and activation of mitophagy in PINK1-/- myocytes. In addition, induction of mitophagy by the atypical BH3-only protein BNIP3 is unaffected by lack of PINK1. Overall, these data suggest that Parkin recruitment to depolarized cardiac mitochondria and subsequent activation of mitophagy is independent of PINK1. Moreover, alternative mechanisms of Parkin activation and pathways of mitophagy remain functional in PINK1-/- myocytes and could compensate for the PINK1 deficiency.     

PINK1/Parkin direct mitochondria to autophagy

Mutations in PTEN-induced putative kinase 1 (PINK1) and PARK2/Parkin cause autosomal recessive forms of Parkinson disease. In mammalian cells, cytosolic Parkin is selectively recruited to depolarized mitochondria, followed by a stimulation of mitochondrial autophagy. We show that Parkin translocation to mitochondria is mediated by PINK1, even in cells with normal mitochondrial membrane potential (ΔΨ_m). Once at the mitochondria, Parkin is in close proximity to PINK1, but Parkin does not catalyze PINK1 ubiquitination nor does PINK1 phosphorylate Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into large mitochondrial perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin and PINK1 modulate mitochondrial trafficking to the perinuclear region, a subcellular area associated with autophagy. Mutations in either Parkin or PINK1 impair this process and, consequently, mitochondrial turnover may be altered, inducing accumulation of defective mitochondria and, ultimately, causing neurodegeneration in Parkinson disease.     

PINK1-Mediated Phosphorylation of Parkin Boosts Parkin Activity in Drosophila

Two genes linked to early onset Parkinson''s disease, PINK1 and Parkin, encode a protein kinase and a ubiquitin-ligase, respectively. Both enzymes have been suggested to support mitochondrial quality control. We have reported that Parkin is phosphorylated at Ser65 within the ubiquitin-like domain by PINK1 in mammalian cultured cells. However, it remains unclear whether Parkin phosphorylation is involved in mitochondrial maintenance and activity of dopaminergic neurons in vivo. Here, we examined the effects of Parkin phosphorylation in Drosophila, in which the phosphorylation residue is conserved at Ser94. Morphological changes of mitochondria caused by the ectopic expression of wild-type Parkin in muscle tissue and brain dopaminergic neurons disappeared in the absence of PINK1. In contrast, phosphomimetic Parkin accelerated mitochondrial fragmentation or aggregation and the degradation of mitochondrial proteins regardless of PINK1 activity, suggesting that the phosphorylation of Parkin boosts its ubiquitin-ligase activity. A non-phosphorylated form of Parkin fully rescued the muscular mitochondrial degeneration due to the loss of PINK1 activity, whereas the introduction of the non-phosphorylated Parkin mutant in Parkin-null flies led to the emergence of abnormally fused mitochondria in the muscle tissue. Manipulating the Parkin phosphorylation status affected spontaneous dopamine release in the nerve terminals of dopaminergic neurons, the survivability of dopaminergic neurons and flight activity. Our data reveal that Parkin phosphorylation regulates not only mitochondrial function but also the neuronal activity of dopaminergic neurons in vivo, suggesting that the appropriate regulation of Parkin phosphorylation is important for muscular and dopaminergic functions.     

Mitochondrial autophagy by Bnip3 involves Drp1-mediated mitochondrial fission and recruitment of Parkin in cardiac myocytes

The Bcl2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) is an atypical BH3-only protein that is associated with mitochondrial dysfunction and cell death. Bnip3 is also a potent inducer of mitochondrial autophagy, and in this study we have investigated the mechanisms by which Bnip3 induces autophagy in cardiac myocytes. We found that Bnip3 induced mitochondrial translocation of dynamin-related protein 1 (Drp1), a protein involved in mitochondrial fission in adult myocytes. Drp1-mediated mitochondrial fission correlated with increased autophagy, and inhibition of Drp1 reduced Bnip3-mediated autophagy. Overexpression of Drp1K38E, a dominant negative of Drp1, or mitofusin 1 prevented mitochondrial fission and autophagy by Bnip3. Also, inhibition of mitochondrial fission or autophagy resulted in increased death of myocytes overexpressing Bnip3. Moreover, Bnip3 promoted translocation of the E3 ubiquitin ligase Parkin to mitochondria, which was prevented in the presence of a Drp1 inhibitor. Interestingly, induction of autophagy by Bnip3 was reduced in Parkin-deficient myocytes. Thus our data suggest that induction of autophagy in response to Bnip3 is a protective response activated by the cell that involves Drp1-mediated mitochondrial fission and recruitment of Parkin.     

Hidden phenotypes of PINK1/Parkin knockout mice

PINK1, a serine/threonine ubiquitin kinase, and Parkin, an E3 ubiquitin ligase, work in coordination to target damaged mitochondria to the lysosome in a process called mitophagy. This review will cover what we have learned from PINK1 and Parkin knockout (KO) mice. Systemic PINK1 and Parkin KO mouse models haven’t faithfully recapitulated early onset forms of Parkinson’s disease found in humans with recessive mutations in these genes. However, the utilization of these mouse models has given us insight into how PINK1 and Parkin contribute to mitochondrial quality control and function in different tissues beyond the brain such as in heart and adipose tissue. Although PINK1 and Parkin KO mice have been generated over a decade ago, these models are still being used today to creatively elucidate cell-type specific functions. Recently, these mouse models have uncovered that these proteins contribute to innate immunity and cancer phenotypes.