Post-translational Modifications of Key Machinery in the Control of Mitophagy.

Mitophagy refers to the process of selective removal of damaged or superfluous mitochondria via the autophagy/lysosome pathway. In the past decade the molecular mechanisms underlying mitophagy have been extensively studied. It is now well established that the key mitophagy machinery undergoes extensive post-translational modifications (PTMs) such as phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation that involve an array of enzymes including protein kinases/phosphatases, E3 ligases/deubiquitinases, acetyltransferases/deacetylases. In this review we provide a systematic summary of these key PTMs, and discuss the effectors and the functional implications of such PTMs in mitophagy-related diseases. Understanding PTM of the mitophagy machinery offers a unique window of opportunity for the discovery of novel mitophagy interventional strategies and for the control of mitophagy-related diseases.

Uncovering individual variations in bystander intervention of injustice through intrinsic brain connectivity patterns.

When confronted with injustice, individuals often intervene as third parties to restore justice by either punishing the perpetrator or helping the victim, even at their own expense. However, little is known about how individual differences in third-party intervention propensity are related to inter-individual variability in intrinsic brain connectivity patterns and how these associations vary between help and punishment intervention. To address these questions, we employed a novel behavioral paradigm in combination with resting-state fMRI and inter-subject representational similarity analysis (IS-RSA). Participants acted as third-party bystanders and needed to decide whether to maintain the status quo or intervene by either helping the disadvantaged recipient (Help condition) or punishing the proposer (Punish condition) at a specific cost. Our analyses focused on three brain networks proposed in the third-party punishment (TPP) model: the salience (e.g., dorsal anterior cingulate cortex, dACC), central executive (e.g., dorsolateral prefrontal cortex, dlPFC), and default mode (e.g., dorsomedial prefrontal cortex, dmPFC; temporoparietal junction, TPJ) networks. IS-RSA showed that individual differences in resting-state functional connectivity (rs-FC) patterns within these networks were associated with the general third-party intervention propensity. Moreover, rs-FC patterns of the right dlPFC and right TPJ were more strongly associated with individual differences in the helping propensity rather than the punishment propensity, whereas the opposite pattern was observed for the dmPFC. Post-hoc predictive modeling confirmed the predictive power of rs-FC in these regions for intervention propensity across individuals. Collectively, these findings shed light on the shared and distinct roles of key regions in TPP brain networks at rest in accounting for individual variations in justice-restoring intervention behaviors.

Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures.

AIMS: This study aimed to illuminate the neuropathological landscape of attention deficit hyperactivity disorder (ADHD) by a multiscale macro-micro-molecular perspective from in vivo neuroimaging data. METHODS: The "ADHD-200 initiative" repository provided multi-site high-quality resting-state functional connectivity (rsfc-) neuroimaging for ADHD children and matched typically developing (TD) cohort. Diffusion mapping embedding model to derive the functional connectome gradient detecting biologically plausible neural pattern was built, and the multivariate partial least square method to uncover the enrichment of neurotransmitomic, cellular and chromosomal gradient-transcriptional signatures of AHBA enrichment and meta-analytic decoding. RESULTS: Compared to TD, ADHD children presented connectopic cortical gradient perturbations in almost all the cognition-involved brain macroscale networks (all pBH <0.001), but not in the brain global topology. As an intermediate phenotypic variant, such gradient perturbation was spatially enriched into distributions of GABAA/BZ and 5-HT2A receptors (all pBH <0.01) and co-varied with genetic transcriptional expressions (e.g. DYDC2, ATOH7, all pBH <0.01), associated with phenotypic variants in episodic memory and emotional regulations. Enrichment models demonstrated such gradient-transcriptional variants indicated the risk of both cell-specific and chromosome- dysfunctions, especially in enriched expression of oligodendrocyte precursors and endothelial cells (all pperm <0.05) as well enrichment into chromosome 18, 19 and X (pperm <0.05). CONCLUSIONS: Our findings bridged brain macroscale neuropathological patterns to microscale/cellular biological architectures for ADHD children, demonstrating the neurobiologically pathological mechanism of ADHD into the genetic and molecular variants in GABA and 5-HT systems as well brain-derived enrichment of specific cellular/chromosomal expressions.

Sampling inequalities affect generalization of neuroimaging-based diagnostic classifiers in psychiatry.

BACKGROUND: The development of machine learning models for aiding in the diagnosis of mental disorder is recognized as a significant breakthrough in the field of psychiatry. However, clinical practice of such models remains a challenge, with poor generalizability being a major limitation. METHODS: Here, we conducted a pre-registered meta-research assessment on neuroimaging-based models in the psychiatric literature, quantitatively examining global and regional sampling issues over recent decades, from a view that has been relatively underexplored. A total of 476 studies (n = 118,137) were included in the current assessment. Based on these findings, we built a comprehensive 5-star rating system to quantitatively evaluate the quality of existing machine learning models for psychiatric diagnoses. RESULTS: A global sampling inequality in these models was revealed quantitatively (sampling Gini coefficient (G) = 0.81, p < .01), varying across different countries (regions) (e.g., China, G = 0.47; the USA, G = 0.58; Germany, G = 0.78; the UK, G = 0.87). Furthermore, the severity of this sampling inequality was significantly predicted by national economic levels (ß = - 2.75, p < .001, R2adj = 0.40; r = - .84, 95% CI: - .41 to - .97), and was plausibly predictable for model performance, with higher sampling inequality for reporting higher classification accuracy. Further analyses showed that lack of independent testing (84.24% of models, 95% CI: 81.0-87.5%), improper cross-validation (51.68% of models, 95% CI: 47.2-56.2%), and poor technical transparency (87.8% of models, 95% CI: 84.9-90.8%)/availability (80.88% of models, 95% CI: 77.3-84.4%) are prevailing in current diagnostic classifiers despite improvements over time. Relating to these observations, model performances were found decreased in studies with independent cross-country sampling validations (all p < .001, BF10 > 15). In light of this, we proposed a purpose-built quantitative assessment checklist, which demonstrated that the overall ratings of these models increased by publication year but were negatively associated with model performance. CONCLUSIONS: Together, improving sampling economic equality and hence the quality of machine learning models may be a crucial facet to plausibly translating neuroimaging-based diagnostic classifiers into clinical practice.

Natural compounds modulating mitophagy: Implications for cancer therapy.

Cancer is considered as the second leading cause of mortality, and cancer incidence is still growing rapidly worldwide, which poses an increasing global health burden. Although chemotherapy is the most widely used treatment for cancer, its effectiveness is limited by drug resistance and severe side effects. Mitophagy is the principal mechanism that degrades damaged mitochondria via the autophagy/lysosome pathway to maintain mitochondrial homeostasis. Emerging evidence indicates that mitophagy plays crucial roles in tumorigenesis, particularly in cancer therapy. Mitophagy can exhibit dual effects in cancer, with both cancer-inhibiting or cancer-promoting function in a context-dependent manner. A variety of natural compounds have been found to affect cancer cell death and display anticancer properties by modulating mitophagy. In this review, we provide a systematic overview of mitophagy signaling pathways, and examine recent advances in the utilization of natural compounds for cancer therapy through the modulation of mitophagy. Furthermore, we address the inquiries and challenges associated with ongoing investigations concerning the application of natural compounds in cancer therapy based on mitophagy. Overcoming these limitations will provide opportunities to develop novel interventional strategies for cancer treatment.

Targeting mitophagy to promote apoptosis is a potential therapeutic strategy for cancer.

Many anticancer agents exert cytotoxicity and trigger apoptosis through the induction of mitochondrial dysfunction. Mitophagy, as a key mitochondrial quality control mechanism, can remove damaged mitochondria in an effective and timely manner, which may result in drug resistance. Although the implication of mitophagy in neurodegenerative diseases has been extensively studied, the role and mechanism of mitophagy in tumorigenesis and cancer therapy are largely unknown. In a recent study, we found that the inhibition of PINK1-PRKN-mediated mitophagy can significantly enhance the anticancer efficacy of magnolol, a natural product with potential anticancer properties. On the one hand, magnolol can induce severe mitochondrial dysfunction, including mitochondrial depolarization, excessive mitochondrial fragmentation and the generation of mitochondrial ROS, leading to apoptosis. On the other hand, magnolol induces PINK1-PRKN-dependent mitophagy via activation of two rounds of feedforward amplification loops. The blockage of mitophagy through genetic or pharmacological approaches promotes rather than attenuates magnolol-induced cell death. Furthermore, inhibition of mitophagy by using distinct inhibitors targeting different mitophagic stages effectively enhances magnolol's anticancer efficacy in vivo. Taken together, our findings strongly indicate that manipulation of mitophagy in cancer treatment will be a promising therapeutic strategy for overcoming cancer drug resistance and improving the therapeutic efficacy of anticancer agents.

Platycodin-D exerts its anti-cancer effect by promoting c-Myc protein ubiquitination and degradation in gastric cancer.

Platycodin D (PD) is a triterpene saponin extracted from the root of Platycodon grandiflorum. It has been reported to exhibit multiple pharmacological and biological properties. There is substantial evidence to support that PD displays a wide range of anti-tumor activities. However, the detailed molecular mechanism still needs further elaboration. In the present study, to explore whether PD inhibits gastric cancer (GC) cell viability, eight GC cell lines and the GES-1 cell line (a gastric mucosal cell line) were tested. We found that PD exhibited better inhibitory activity on GC cell lines than on the non-tumor cell line. Besides, treatment with PD led to a significant cell cycle arrest, thereby causing subsequent apoptosis. Regarding the cell growth inhibition mechanism, PD can downregulate the protein level of c-Myc rather than its mRNA level in a dose-dependent manner. Further studies revealed that PD disturbed the overall ubiquitination level in GC cell lines and enhanced the ubiquitination-dependent degradation of c-Myc. Interestingly, the inhibition of cell viability by PD could be restored to a certain extent when the expression of c-Myc was recovered, suggesting that PD-mediated GC cell growth inhibition is closely associated with c-Myc expression. Our study proposes a novel molecular mechanism for PD inhibiting GC cell proliferation and growth by destabilizing the c-Myc protein. This work may lay a preliminary foundation for developing PD as an anti-cancer therapy.

Computational insights into the selectivity mechanism of APP-IP over matrix metalloproteinases.

In this work, selectivity mechanism of APP-IP inhibitor (ß-amyloid precursor protein-derived inhibitory peptide) over matrix metalloproteinases (MMPs including MMP-2, MMP-7, MMP-9 and MMP-14) was investigated by molecular modeling methods. Among MMPs, MMP-2 is the most favorable one for APP-IP interacting based on our calculations. The predicted binding affinities can give a good explanation of the activity difference of inhibitor APP-IP. In Comparison with MMP-2/APP-IP complex, the side chain of Tyr214(MMP-7) makes the binding pocket so shallow that the whole side chain of Tyr3(APP-IP) can not be fully embraced, thus unfavorable for the N-terminal of APP-IP binding to MMP-7. The poor selectivity of APP-IP toward MMP-9 is mainly related with the decrease of interaction between the APP-IP C-terminal and MMP-9 due to the bulky side chains of Pro193 and Gln199, which is in agreement with experiment. The mutations at residues P193A and Q199G of MMP-9 alternate the binding pattern of the C-terminal of APP-IP by forming two new hydrogen bonds and hydrophobic interactions with MMP-9. The mutants favor the binding affinity of MMP-9 largely. For MMP-14/APP-IP, the large steric effect of Phe204(MMP-14) and the weak contributions of the polar residues Asn231(MMP-14) and Thr190(MMP-14) could explain why MMP-14 is non-selective for APP-IP interacting. Here, the molecular modeling methods were successfully employed to explore the selective inhibitor of MMPs, and our work gives valuable information for future rational design of selective peptide inhibitors toward individual MMP.

Improving adaptive response to negative stimuli through non-emotional working memory training.

People with high working memory (WM) capacity tend to respond proactively and experience a decrease in undesired emotions, implying the potential influence of WM training on emotional responses. Although training emotional WM could enhance emotional control, the training also improves emotional response itself. Thus, the far-transfer effects of non-emotional WM training on emotional responses remain an open question. In the present study, two experiments were conducted to detect these effects. The Preliminary experiment matched the expectations of the gains of the training tasks between the experimental and active control groups (n = 33). In Experiments 1 and 2, participants performed 7-day and 15-day training procedures, respectively. Results indicated that after a 7-day training, non-emotional WM training (n = 17) marginally reduced individuals' emotional responses compared with the active control group (n = 18); importantly, this improvement became significant after a 15-day training (n (WM training) = 20, n (active control) = 18). A combination analysis for Experiments 1 and 2 showed that training gains on WM performance were significantly related to reduced emotional responses (r = -0.359), indicating a dosage effect. Therefore, non-emotional WM training provides a safe and effective way to enhance adaptive emotional responses.

From reversal to normal: Robust improvement in conflict adaptation through real-time functional near infrared spectroscopy-based neurofeedback training.

Conflict adaptation refers to the improved conflict control induced after experiencing conflict and is a prominent index of adaptive cognitive control. Reversal of conflict adaptation may be maladaptive and predictive of certain mental disorders. Here, we employed real-time functional near infrared spectroscopy-based neurofeedback training, with the left dorsolateral prefrontal cortex as the target brain area, to investigate whether reversal of conflict adaptation during a word-color Stroop task could be recovered to be normal. Healthy human individuals with reversal pattern of conflict adaptation in the pretest were randomly assigned into the experimental or control groups. Distributed training for 80 min led to greater improvements in the experimental group who received real neurofeedback compared to those in the control group who received sham neurofeedback. These results indicated causal evidence for understanding the generation of conflict adaptation and heighten the prospects of clinical application of neurofeedback training.

Improving Emotion Regulation Through Real-Time Neurofeedback Training on the Right Dorsolateral Prefrontal Cortex: Evidence From Behavioral and Brain Network Analyses.

We investigated if emotion regulation can be improved through self-regulation training on non-emotional brain regions, as well as how to change the brain networks implicated in this process. During the training period, the participants were instructed to up-regulate their right dorsolateral prefrontal cortex (rDLPFC) activity according to real-time functional near-infrared spectroscopy (fNIRS) neurofeedback signals, and there was no emotional element. The results showed that the training significantly increased emotion regulation, resting-state functional connectivity (rsFC) within the emotion regulation network (ERN) and frontoparietal network (FPN), and rsFC between the ERN and amygdala; however, training did not influence the rsFC between the FPN and the amygdala. However, self-regulation training on rDLPFC significantly improved emotion regulation and generally increased the rsFCs within the networks; the rsFC between the ERN and amygdala was also selectively increased. The present study also described a safe approach that may improve emotion regulation through self-regulation training on non-emotional brain regions.

Error-induced adaptability: Behavioral and neural dynamics of response-stimulus interval modulations on posterror slowing.

Response errors often cause individuals to slow down their subsequent reactions (posterror slowing [PES]). Despite intensive investigations on PES, the adaptive nature of PES remains unresolved. Here, we systematically examined this issue by manipulating response-stimulus intervals (RSIs) and examining their influence on behaviors and neural dynamics of PES. Behavioral and electrophysiological (EEG) measures were recorded while male and female human participants performed a four-choice flanker task as RSIs were manipulated. Behaviorally, PES showed maladaptive features at short RSIs but some adaptive features at long RSIs. EEG results indicated that RSIs did not affect basic error-related processing, indexed by the same pattern in the contrasts between flanker errors and correct responses on the error-related negativity (ERN), error positivity (Pe), or theta band, no matter at short or long RSIs. However, RSIs significantly influenced postflanker error attentional adjustment, motor inhibition, and sensory sensitivity. At short RSIs, compared with postcorrect trials, postflanker error trials elicited larger beta band power and smaller P1 amplitude but did not affect alpha band power, suggesting that motor processing was inhibited, and subsequent sensory processing was impaired, but no attentional adjustment occurred. By contrast, at long RSIs, postflanker error trials led to smaller alpha and beta band power but did not affect P1 amplitude, indicating that attentional adjustment but not motor inhibition occurred, and sensory processing was not impaired. Together with behavioral results, the current study demonstrated that PES was adaptive at long RSIs but maladaptive at short RSIs. We further discuss the role of central resources in the adaptability of PES. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A hybrid platform featuring nanomagnetic ligand fishing for discovering COX-2 selective inhibitors from aerial part of Saussurea laniceps Hand.-Mazz.

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea laniceps Hand.-Mazz. (Compositae) is a representative "snow lotus" herb well known in Chinese folk medicine to treat inflammation-related diseases such as arthritis. S. laniceps (SL) shows anti-inflammatory and analgesic potencies and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. The herb is a valuable source of natural alternatives to synthetic COX-2 selective nonsteroidal anti-inflammatory drugs, a common medication for rheumatoid arthritis (RA) and osteoarthritis (OA) reported with serious cardiovascular side effects. AIM OF THE STUDY: Based on an innovative drug screening platform, this study aimed to discover safe, effective COX-2 selective inhibitors from SL. MATERIALS AND METHODS: An enzyme-anchored nanomagnetic fishing assay was developed to separate COX-2 ligands from SL. Cell and animal models of cardiomyocytes, lipopolysaccharide-stimulated macrophages, rat adjuvant-induced arthritis, and anterior cruciate ligament transection-induced OA rats, were adopted to screen the single/combined ligands regarding toxicity and bioactivity levels. Molecular docking was employed to unravel binding mechanisms of the ligands towards COX-1 and COX-2. RESULTS: Four COX-2 selective compounds were separated from SL using optimized COX-2-functionalized magnetic nanoparticles. All the four ligands were proved with evidently lower cardiotoxicity both in vitro and in vivo than celecoxib, a known COX-2 selective inhibitor. Two ligands, scopoletin and syringin, exhibited potent anti-arthritic activities in rat models of RA and OA by alleviating clinical statuses, immune responses, and joint pathological features; their optimum combination ratio was discovered with stronger remedial effects on rat OA than single administrations. The COX-1/2 binding modes of the two phytochemicals contributed to explain their cardiac safety and therapeutic performances. CONCLUSIONS: The screened chemicals are promising to be developed as COX-2 selective inhibitors as part of treating RA and OA. The hybrid strategy for discovering therapeutic agents from SL is shown here to be efficient; it should be equally valuable for finding other active chemicals in other natural sources.

Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy.

Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal Magnolia officinalis. First, we found that magnolol induces mitochondrial depolarization, causes excessive mitochondrial fragmentation, and increases mitochondrial reactive oxygen species (mtROS). Second, magnolol induces PTEN-induced putative kinase protein 1 (PINK1)‒Parkin-mediated mitophagy through regulating two positive feedforward amplification loops. Third, magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway. Moreover, magnolol prolongs the survival time of tumor-bearing mice. Finally, inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy, both in vitro and in vivo. Altogether, our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis, whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol, suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.

N-Back Task Training Helps to Improve Post-error Performance.

Improved performance on working memory (WM) through training has been widely expected to transfer to other domains. Recent studies have proposed that WM training could enhance the autonomous coordination of WM processes. Based on the shared processes between WM and error processing, our present study explored the transfer effect of 15 days of training on post-error performance, during the n-back task, compared to a simple visual search task. Participants were randomly assigned to either the training (N = 22) or control (N = 18) group. We found that WM training successfully improved WM performance. After training, compared with the control group, the training group showed a significant reduction in post-error slowing (PES); however, post-error accuracy and the flanker effect were not modulated by WM training. Moreover, we observed a significant, negative correlation between the changes in PES and WM from pretest to posttest and classified two groups based on these changes in PES with 70% accuracy. Thus, in our present sample, WM training improved post-error performance. We propose that the skill of controlling information flow, developed during WM training, is transferable to other tasks and discuss the implications of current findings for understanding the generation of PES.

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.

Bone marrow stromal cell-derived growth inhibitor serves as a stress sensor to induce autophagy.

Autophagy is an evolutionarily conserved stress response that promotes the lysosomal degradation of intracellular components. The bone marrow stromal cell-derived growth inhibitor (BDGI) functions as a stress sensor which is upregulated by oxidative stress and DNA damage. However, the role of BDGI in autophagic response to certain stresses remains unknown. Here, our results demonstrate that BDGI defines the impact of autophagy induction under stresses. Overexpression of BDGI promotes, while knockdown of BDGI impairs, autophagy. Mechanistically, BDGI localizes to the nucleus and interacts with the transcription factor transcription factor EB to increase the expression of multiple autophagy- and lysosome-related genes. In addition, BDGI regulates autophagy in a p53-dependent manner. Furthermore, BDGI-induced autophagy enables cell survival under stress conditions. Taken together, our study demonstrates that BDGI is a stress sensor that positively regulates autophagy.

Characterization of Chemical Component Variations in Different Growth Years and Tissues of Morindae Officinalis Radix by Integrating Metabolomics and Glycomics.

Morindae Officinalis Radix (MOR), the dried root of Morinda officinalis F.C. How (Rubiaceae), is a popular food supplement in southeastern China for bone protection, andrological, and gynecological healthcare. In clinical use, 3-4 year old MOR is commonly used and the xylem is sometimes removed. However, there is no scientific rationale for these practices so far. In this study, metabolomics and glycomics were integrated using multiple chromatographic and mass spectrometric techniques coupled with multivariate statistical analysis to investigate the qualitative and quantitative variations of secondary metabolome and glycome in different growth years (1-7 years) and tissues (xylem and cortex) of MOR. The results showed that various types of bioactive components reached a maximum between 3 and 4 years of growth and that the xylem contained more potentially toxic constituents but less bioactive components than the cortex. This study provides the chemical basis for the common practice of using 3-4 year old MOR with the xylem removed.

PTEN-L puts a brake on mitophagy.

Mitophagy is a main type of selective autophagy, via which damaged mitochondria are selectively degraded via the autophagic pathway. The protein kinase PINK1 and E3 ubiquitin ligase PRKN are the most well studied regulators of mitophagy, via a feedforward mechanism involving ubiquitin phosphorylation (p-Ser65-Ub) and accumulation at the damaged mitochondria. However, it is unknown whether there is a protein phosphatase against PINK1-mediated phosphorylation of ubiquitin. We recently reported that PTEN-L, a newly identified PTEN isoform, is a novel negative regulator of mitophagy through dephosphorylation of p-Ser65-Ub. Our data demonstrate that a significant portion of PTEN-L localizes at the outer mitochondrial membrane and is able to prevent PRKN's mitochondrial translocation, reduce the phosphorylation of PRKN, impair its E3 ligase activity as well as maintain PRKN in a closed/inactive status. Moreover, we found that PTEN-L dephosphorylates p-Ser65-Ub to disrupt the feedforward mechanism of mitophagy. Our findings suggest that PTEN-L acts as a brake in the regulation of mitophagy. ABBREVIATIONS: ATR: alternatively translated region; CCCP: carbonylcyanide 3-chlorophenylhydrazone; DUBs: deubiquitinating enzymes; MFN2: mitofusion2; MS/MS: tandem mass spectrometry; mtDNA: mitochondrial DNA; MTS: mitochondrial targeting sequences; O/A: oligomycin and antimycin A; PINK1: PTEN induced putative kinase 1; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PTEN: phosphatase and tensin homolog; PTEN-L: phosphatase and tensin homolog-long; Ub: ubiquitin; USP: ubiquitin-specific proteases; YFP: yellow fluorescence protein.

Author Correction: PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1-Parkin-mediated mitophagy.

We apologize for three errors that we just found in the paper published online on 22 June 2018.