Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.

Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early-onset Parkinson's disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin (Ub) ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane forming a high-molecular-weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates Ub, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 N-terminal-C-terminal extension module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.

The impact of the COVID-19 pandemic on eating disorders: A systematic review.

OBJECTIVE: A growing body of evidence suggests that individuals with eating disorders (EDs) have experienced deteriorating symptoms, increased isolation, and an increase in hospital admissions as a result of the COVID-19 pandemic. Despite this, no systematic reviews have been conducted examining the COVID-19 and ED peer-reviewed literature. Therefore, this systematic review aimed to synthesize the impact of the COVID-19 pandemic on individuals with EDs. METHOD: Database searches of the peer-reviewed literature were completed in the subsequent databases: CINAHL, Embase, MEDLINE, and PsycINFO (from November 2019 to October 20, 2021). All research reporting on the relationship between the COVID-19 pandemic on individuals with EDs were included. RESULTS: Fifty-three studies met the inclusion criteria, including 36,485 individuals with EDs. The pooled hospital admissions across the studies demonstrated on average a 48% (pre = 591, post = 876, n = 10 studies) increase in admissions during the pandemic compared to previous pre-pandemic timepoints. In this review, 36% of studies (n = 19) documented increases in eating disorder symptoms during the pandemic, this increase in eating disorder symptoms were documented in AN, BED, BN, and OFSED patients. Studies also demonstrated increases in anxiety (n = 9) and depression (n = 8), however patterns of change appeared to be diagnostic and timing specific (e.g., lockdowns). DISCUSSION: We found a large increase in the number of hospitalizations and an increase in ED symptoms, anxiety, depression, and changes to BMI in ED patients during the pandemic. However, these changes appeared to be diagnostic and timing specific. Many qualitative studies described deterioration in ED symptomatology due to decreased access to care and treatment, changes to routine and loss of structure, negative influence of the media, and social isolation. Future studies are needed to focus on pediatric populations, new ED diagnoses, and severity of illness at presentation. PUBLIC SIGNIFICANCE: The scientific literature suggests that individuals with eating disorders have experienced deteriorating symptoms, increased isolation, and an increase in hospital admissions as a result of the COVID-19 pandemic. This study synthesized 53 articles and explored the impact of the COVID-19 pandemic on patients with eating disorders. We found increases in eating disorder symptoms during the pandemic; this increase in eating disorder symptoms was documented in patients with common eating disorders including anorexia nervosa, binge-eating disorder, bulimia nervosa, and other specified feeding and eating disorders. This review also demonstrated changes in body mass index (an index used to classify underweight, overweight, and obesity in adults) and increases in anxiety and depression during the pandemic compared to previous timepoints; patterns of change appeared to be related to timing of lockdowns. This review provides important information on the impact of COVID-19 on the physical and mental health of individuals with eating disorders.

OBJETIVO: Un creciente conjunto de evidencia sugiere que las personas con trastornos de la conducta alimentaria (TCA) han experimentado síntomas de deterioro, mayor aislamiento y un aumento en los ingresos hospitalarios como resultado de la pandemia de COVID-19. A pesar de esto, no se han realizado revisiones sistemáticas que examinen la literatura revisada por pares de COVID-19 y TCA. Por lo tanto, esta revisión sistemática tuvo como objetivo sintetizar el impacto de la pandemia de COVID-19 en las personas con TCA. MÉTODO: Las búsquedas en las bases de datos de la literatura revisada por pares se completaron en las bases de datos posteriores: CINAHL, Embase, MEDLINE y PsycINFO (de noviembre de 2019 al 20 de octubre de 2021). Se incluyeron todos los informes de investigación sobre la relación entre la pandemia de COVID-19 en individuos con TCA. RESULTADOS: Cincuenta y tres estudios cumplieron los criterios de inclusión, incluyendo 36,485 individuos con TCA. Los ingresos hospitalarios agrupados en los estudios demostraron en promedio un aumento del 48% (antes = 591, después = 876, n = 10 estudios) en los ingresos durante la pandemia en comparación con los puntos de tiempo previos a la pandemia. En esta revisión, el 36% de los estudios (n = 19) documentaron aumentos en los síntomas del trastorno alimentario durante la pandemia, este aumento en los síntomas del trastorno de la conducta alimentaria se documentó en pacientes con AN, TpA, BN y OSFED. Los estudios también demostraron aumentos en la ansiedad (n = 9) y la depresión (n = 8), sin embargo, los patrones de cambio parecían ser diagnósticos y específicos del momento (por ejemplo, encierros). DISCUSIÓN: Encontramos un gran aumento en el número de hospitalizaciones y un aumento en los síntomas de TCA, ansiedad, depresión y los cambios en el IMC en pacientes con TCA durante la pandemia. Sin embargo, estos cambios parecían ser diagnósticos y específicos del momento. Muchos estudios cualitativos describieron un deterioro en la sintomatología del trastorno de la conducta alimentaria (TCA) debido a la disminución del acceso a la atención y el tratamiento, los cambios en la rutina y la pérdida de estructura, la influencia negativa de los medios de comunicación y el aislamiento social. Se necesitan estudios futuros para centrarse en las poblaciones pediátricas, los nuevos diagnósticos de TCA y la gravedad de la enfermedad al momento de la presentación. PALABRAS CLAVE: trastornos de la conducta alimentaria, pandemia, COVID-19.

A molecular dialogue between local translation and mitochondria: powering mitophagy in axons.

Mitochondrial quality control is a key element of neuronal health and viability. When left untouched, defective mitochondria can initiate neuronal degeneration. Cytosolic proteins PINK1 and Parkin comprise one key pathway responsible for clearing damaged mitochondria. Neurons, however, pose a unique challenge to this process because proteins need to be abundantly available at locations distant from the cell body. Recent study has confirmed that local translation of PINK1 in axons and dendrites is the solution. Pink1 transcripts are tethered to mitochondria via SYNJ2a and active translation, then subsequently co-transported to distal locations. Once arriving in the neuron's periphery, local translation of PINK1 can facilitate mitophagy and ultimately sustain mitochondrial health.

Mitochondrial import stress and PINK1-mediated mitophagy: the role of the PINK1-TOMM-TIMM23 supercomplex.

Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.

How does mitochondrial import machinery fine-tune mitophagy? Different paths and one destination.

Given their polyvalent roles, an intrinsic challenge that mitochondria face is the continuous exposure to various stressors including mitochondrial import defects, which leads to their dysfunction. Recent work has unveiled a presequence translocase-associated import motor (PAM) complex-dependent quality control pathway whereby misfolded proteins mitigate mitochondrial protein import and subsequently elicit mitophagy without the loss of mitochondrial membrane potential.

Dephosphorylation Targeting Chimaera (DEPTAC): Targeting Tau Proteins in Tauopathies.

One salient hallmark of neurodegeneration is the accumulation of toxic protein aggregates in neuronal cells. This proteotoxicity culminates in the deterioration of neuronal function. In AD and related tauopathies, the microtubule-associated protein tau becomes hyperphosphorylated. Hyperphosphorylated tau forms neurofibrillary tangles (NFTs) within neurons, which constitute a unique feature of tauopathies, including AD. A recent study has exploited a novel molecular strategy to counteract hyperphosphorylated tau and enhance its degradation. Analogous to the PROTAC methodology, a novel dephosphorylation targeting chimera (DEPTAC) was designed to promote the molecular interaction between tau and phosphatase, which, in turn, augments its degradation. Herein, we briefly discuss this novel finding and its potential therapeutic implications.

The prevalence of substance use disorders and substance use in anorexia nervosa: a systematic review and meta-analysis.

AIM: Individuals with anorexia nervosa (AN) often present with substance use and substance use disorders (SUDs). However, the prevalence of substance use and SUDs in AN has not been studied in-depth, especially the differences in the prevalence of SUDs between AN types [e.g., AN-R (restrictive type) and AN-BP (binge-eating/purge type]. Therefore, this systematic review and meta-analysis aimed to assess the prevalence of SUDs and substance use in AN samples. METHOD: Systematic database searches of the peer-reviewed literature were conducted in the following online databases: MEDLINE, PsycINFO, Embase, and CINAHL from inception to January 2021. We restricted review eligibility to peer-reviewed research studies reporting the prevalence for either SUDs or substance use in individuals with AN. Random-effects meta-analyses using Freeman-Tukey double arcsine transformations were performed on eligible studies to estimate pooled proportions and 95% confidence intervals (CIs). RESULTS: Fifty-two studies met the inclusion criteria, including 14,695 individuals identified as having AN (mean age: 22.82 years). Random pooled estimates showed that substance use disorders had a 16% prevalence in those with AN (AN-BP = 18% vs. AN-R = 7%). Drug abuse/dependence disorders had a prevalence of 7% in AN (AN-BP = 9% vs. AN-R = 5%). In studies that looked at specific abuse/dependence disorders, there was a 10% prevalence of alcohol abuse/dependence in AN (AN-BP = 15% vs. AN-R = 3%) and a 6% prevalence of cannabis abuse/dependence (AN-BP = 4% vs. AN-R = 0%). In addition, in terms of substance use, there was a 37% prevalence for caffeine use, 29% prevalence for alcohol use, 25% for tobacco use, and 14% for cannabis use in individuals with AN. CONCLUSION: This is the most comprehensive meta-analysis on the comorbid prevalence of SUDs and substance use in persons with AN, with an overall pooled prevalence of 16%. Comorbid SUDs, including drugs, alcohol, and cannabis, were all more common in AN-BP compared to AN-R throughout. Therefore, clinicians should be aware of the high prevalence of SUD comorbidity and substance use in individuals with AN. Finally, clinicians should consider screening for SUDs and integrating treatments that target SUDs in individuals with AN. Individuals with anorexia nervosa (AN) may also present with substance use or have a substance use disorder (SUDs). Thus, we conducted a systematic review and meta-analysis to determine the prevalence of substance use and substance use disorders in individuals with AN. We examined published studies that reported the prevalence of either substance use or SUDs in individuals with AN. We found that substance use disorders had a 16% prevalence and that drug abuse/dependence disorders had a prevalence of 7% in those with AN. These rates were much higher in individuals with binge-eating/purging type compared to the restrictive AN. However, many specific substance use disorders and substance use types were low in individuals with AN. Nonetheless, clinicians should be aware of the high prevalence of SUD comorbidity and substance use in individuals with AN.

The Prevalence of Impulse Control Disorders and Behavioral Addictions in Eating Disorders: A Systematic Review and Meta-Analysis.

Aim: Individuals with eating disorders (EDs) may present with impulse control disorders (ICDs) and behavioral addictions (BAs), which may result in additional suffering and treatment resistance. However, the prevalence of ICDs and BAs in EDs has not been systematically examined. Therefore, this systematic review and meta-analysis aimed to assess the prevalence of ICDs and BAs in ED samples. Methods: A comprehensive electronic database search of the peer-reviewed literature was conducted in the following online databases: MEDLINE, PsycINFO, Embase, and CINAHL from their inception to May 2021. We restricted review eligibility to research studies reporting prevalence for ICDs or BAs in individuals with diagnosed EDs. The outcome for this review was the prevalence of ICDs or BAs in individuals with EDs. A series of random-effects meta-analyses were performed on eligible studies to estimate the pooled proportions and 95% confidence intervals (CIs). Results: Thirty-five studies met the inclusion criteria, including a total of 9,646 individuals identified as having an ED, 18 of these studies specifically examined ICDs/BAs in AN, BN, and BED. Random-effects pooled estimates demonstrated that the comorbid prevalence of any ICD was 22%. The prevalence of comorbid pathological/compulsive buying was highest (19%), followed by kleptomania (18%), pathological internet use (12%), intermittent explosive disorder (4%), trichotillomania (3%), and gambling disorder (2%). In addition, the prevalence of stealing/shoplifting behaviors was 30% in those with EDs. Conclusion: This is the first meta-analysis on the comorbid prevalence of EDs and ICDs/BAs. We found a moderate prevalence for these comorbid conditions, with approximately one out of five individuals with an ED also displaying a comorbid ICD/BA. Although causal inferences cannot be drawn, the numbers strongly suggest that clinical screening/monitoring of ICDs/BAs should be part of the clinical routine in cohorts with EDs. ED settings need either the capacity to manage these disorders or adequate access to relevant services. Further investigations are needed to reveal common underlying pathomechanisms. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42020202044.