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There is a need for well-described treatments targeting individuals at risk for suicidal behaviors. The present study aims to investigate the effectiveness of MBCT adapted to individuals who are suicidal (MBCT-S) in a randomized controlled trial, comparing an intervention group receiving MBCT-S and treatment as usual (TAU) with a control group receiving TAU only. Participants who were 18 years or older and experienced suicidal ideation were included. Assessments on suicidal ideation and symptoms associated with suicidal behavior were carried out at baseline, post-treatment, and 12 weeks after the end of the training. When comparing the intervention group with the control group, a significant reduction was found at follow-up in suicidal ideation and depressive symptoms. When focusing on the intervention group only, a significant reduction was found in suicidal ideation, depressive symptoms, hopelessness, worrying, defeat, and entrapment, and a significant increase in mindfulness both at post-treatment and at follow-up. The findings suggest that MBCT-S is a promising suicide-specific intervention as it may have the potential to reduce suicidal ideation and suicide-related components.

Mitochondrial diseases are genetic disorders impairing mitochondrial functions. Here we describe a patient with a neurodegenerative condition associated with myopia, bilateral sensorineural hearing loss and motor disorders. Brain MRIs showed major cortico-subcortical and infra-tentorial atrophies, as well as intracerebral iron accumulation and central calcifications, compatible with a NBIA-like phenotype. Mitochondrial DNA analysis revealed an undescribed variant: m.8091G>A in the MT-CO2 gene, associated with a complex IV deficiency and a decrease of the mitochondrial respiratory chain capabilities. We report here this pathogenic variant, associated with a NBIA-like phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To examine whether sexual and gender minority (SGM) emerging adults perceived their SGM status was linked to suicidal ideation, and to explore if their responses fell within tenets of the minority stress framework., Method: Open text (survey) responses of Dutch and Flemish SGM emerging adults ( n   =  187) were thematically analysed using the constant comparative comparison method for qualitative analysis., Results: We identified 8 themes in our qualitative analysis. Two themes fell within the scope of the minority stress framework that has received little attention: (1) concerns about relationships and family planning and (2) feeling different (internal stressor). Two additional themes emerged largely beyond the scope of existing minority stress framework studies on suicidality: (3) SGM-related questioning; (4) negativity in LGBT communities. Four established minority stress framework themes emerged: (5) gender identity stress; (6) victimization; (7) coming-out stress; (8) psychological difficulties linked to SGM status., Conclusion: Suicide prevention needs to focus on supporting SGM emerging adults who worry about feeling "different", or who have concerns over their romantic and family life, on reducing gender minority stress, as well as on caring for those who are victimized due to their sexual or gender identity.

Introduction: Suicide is a serious public health concern worldwide. Current psychological interventions targeting suicidal ideation and behavior are, however, limited and often lack convincing empirical support. Future-Oriented Group Training (FOGT) targets crucial aspects of the suicidal process, thus possibly offering a promising intervention for suicidal ideation. This study aimed at investigating the short-term and long-term effects of FOGT on suicidal thoughts and related variables., Methods: A randomized controlled trial was conducted, comparing the intervention group (FOGT + treatment as usual (TAU)) to a control group (TAU) at pre and posttreatment and at a 12-week follow-up. Suicidal ideation was the primary outcome, while depressive symptoms, hopelessness, defeat, entrapment, worrying, and the ability for future-oriented thinking were secondary outcomes., Results: When compared to the control group, the intervention group showed significant decreases in worrying at posttreatment and significant increases in future-oriented thinking at follow-up. Pre-post analyses within the intervention group showed significant small-to-medium effects for primary as well as most secondary outcomes. Changes in suicidal ideation, depression, hopelessness, and future-oriented thinking remained significant at follow-up., Conclusion: This study provides promising empirical evidence for the use of FOGT for individuals with suicidal ideation., (© 2023 American Association of Suicidology.)

Objective: This study examined associations of minority stressors (i.e., victimization, internalized homonegativity, and stigma consciousness), and coping styles (i.e., active, avoidant, and passive) with suicidal ideation and suicide attempts (suicidality) among sexual and gender minority (SGM) young adults, and whether coping style moderated these associations., Methods: Logistic regression analyses examined these associations among 1432 SGM young adults (ages 18-29)., Results: Minority stressors and passive coping were associated with a higher likelihood of suicidality. Avoidant coping was associated with a lower likelihood of lifetime suicidal ideation and attempts among sexual minority participants, and active coping with a lower likelihood of past-year suicidal ideation among sexual minority participants. Moderation analyses among sexual minority participants showed that when avoidant coping was high, associations between low victimization (compared with no victimization) and lifetime suicide attempts, and stigma consciousness and lifetime suicide attempts became non-significant, and the association between internalized homonegativity and lifetime suicide attempts became significant. Among gender minority participants, when passive coping was high the association between low victimization and lifetime suicidal ideation became significant., Conclusion: This study underlines the importance of minority stress and coping for suicidality among SGM young adults and the need for more research regarding the role of coping., (© 2022 The Authors. Suicide and Life-Threatening Behavior published by Wiley Periodicals LLC on behalf of American Association of Suicidology.)

Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.

Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.

Sexual minority emerging adults are more likely to engage in suicidal ideation than their heterosexual counterparts. Experiences of homophobic violence are associated with suicidal ideation. Yet, the specific mechanisms linking homophobic violence to suicidal ideation remain unclear. Entrapment and social belongingness were tested to determine their relevance for understanding the link between homophobic violence and suicidal ideation. A sample of sexual minority Dutch emerging adults (N = 675; ages 18-29, M = 21.93 years, SD = 3.20) were recruited through online platforms and flyers. Homophobic violence was expected to be positively associated with suicidal ideation and entrapment. The association between homophobic violence and suicidal ideation was expected to be indirectly linked through entrapment. We explored whether various sources of social belongingness moderated the path between entrapment and suicidal ideation and whether those sources of social belongingness moderated the indirect effect of homophobic violence on suicidal ideation through entrapment. Results showed that homophobic violence and entrapment were positively associated with suicidal ideation and that family belongingness was negatively associated with suicidal ideation. Homophobic violence and suicidal ideation were not indirectly linked through entrapment. The interaction effect between entrapment and family belongingness was significant, suggesting that, on average, the effect of entrapment on suicidal ideation decreased when family belongingness was high. These results suggest that family belongingness may reduce the association between entrapment and suicidal ideation while adjusting for homophonic violence. Reducing entrapment and improving family belongingness may be useful targets for programs aimed at preventing suicidal ideation among sexual minority emerging adults.

Cyberbullying victimization is associated with mental health problems and reported to occur more in nonheterosexual orientation youth (lesbian, gay, bisexual, and questioning (LGBQ)) than among heterosexual youth. Parental support may protect against mental health problems after being victimized, but nonsupportive parental influences may also exacerbate harm. This study investigated whether parenting dimensions (autonomy support, psychological control) moderated the associations between bullying victimization and mental health problems among heterosexual and LGBQ adolescents. An anonymous survey was completed by 1037 adolescents (M age = 15.2 ± 1.9, 50% female). Regression analyses examined associations between victimization, sexual orientation, and mental health problems, and investigated the moderating role of parenting. Both forms of victimization were associated with higher mental health problems. LGBQ youth experienced more depressive symptoms and suicidal ideation than heterosexual youth. Lower levels of parental psychological control and higher levels of autonomy support were related to having fewer mental health problems. However, perceived autonomy support appeared less protective when adolescents experienced more frequent victimization. Moreover, parental psychological control was related to heightened risk for suicidal plans specifically among LGBQ youth and also exacerbated the association between cyberbullying victimization and stress among LGBQ youth. These findings underscore the need to address parenting in whole-school antibullying and mental health promotion programs.

Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.

A non-synonymous mtDNA mutation, m.3395A > G, which changes tyrosine in position 30 to cysteine in p.MT-ND1, was found in several patients with a wide range of clinical phenotypes such as deafness, diabetes and cerebellar syndrome but no Leber's hereditary optic neuropathy. Although this mutation has already been described, its pathogenicity has not been demonstrated. Here, it was found isolated for the first time, allowing a study to investigate its pathogenicity. To do so, we constructed cybrid cell lines and carried out a functional study to assess the possible consequences of the mutation on mitochondrial bioenergetics. Results obtained demonstrated that this mutation causes an important dysfunction of the mitochondrial respiratory chain with a decrease in both activity and quantity of complex I due to a diminution of p.MT-ND1 quantity. However, no subcomplexes were found in cybrids carrying the mutation, indicating that the quality of the complex I assembly is not affected. Moreover, based on the crystal structure of p.MT-ND1 and the data found in the literature, we propose a hypothesis for the mechanism of the degradation of p.MT-ND1. Our study provides new insights into the pathophysiology of mitochondrial diseases and in particular of MT-ND1 mutations., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The basic understanding of the biological effects of eukaryotic translation initiation factors (EIFs) remains incomplete, notably for their roles independent of protein translation. Different EIFs exhibit nuclear localization and DNA-related functions have been proposed, but the understanding of EIFs novel functions beyond protein translation lacks of integrative analyses between the genomic and the proteomic levels. Here, the noncanonical function of EIF3F was studied in human lung adenocarcinoma by combining methods that revealed both the protein-protein and the protein-DNA interactions of this factor. We discovered that EIF3F promotes cell metastasis in vivo. The underpinning molecular mechanisms involved the regulation of a cluster of 34 metastasis-promoting genes including Snail2, as revealed by proteomics combined with immuno-affinity purification of EIF3F and ChIP-seq/Q-PCR analyses. The interaction between EIF3F and signal transducer and activator of transcription 3 (STAT3) controlled the EIF3F-mediated increase in Snail2 expression and cellular invasion, which were specifically abrogated using the STAT3 inhibitor Nifuroxazide or knockdown approaches. Furthermore, EIF3F overexpression reprogrammed energy metabolism through the activation of AMP-activated protein kinase and the stimulation of oxidative phosphorylation. Our findings demonstrate the role of EIF3F in the molecular control of cell migration, invasion, bioenergetics, and metastasis. The discovery of a role for EIF3F-STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma could lead to the development of diagnosis and therapeutic strategies.

The ubiquitin proteasome system (UPS) regulates many cellular functions by degrading key proteins. Notably, the role of UPS in regulating mitochondrial metabolic functions is unclear. Here, we show that ubiquitination occurs in different mitochondrial compartments, including the inner mitochondrial membrane, and that turnover of several metabolic proteins is UPS dependent. We specifically detailed mitochondrial ubiquitination and subsequent UPS-dependent degradation of succinate dehydrogenase subunit A (SDHA), which occurred when SDHA was minimally involved in mitochondrial energy metabolism. We demonstrate that SDHA ubiquitination occurs inside the organelle. In addition, we show that the specific inhibition of SDHA degradation by UPS promotes SDHA-dependent oxygen consumption and increases ATP, malate, and citrate levels. These findings suggest that the mitochondrial metabolic machinery is also regulated by the UPS., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice have been widely used to model the loss of dopaminergic neurons. As this treatment leads to basal ganglia degeneration, it was proposed that MPTP mice could be used as a model of Leigh syndrome. However, this mitochondrial pathology is biochemically characterized by a respiratory chain dysfunction. To determine if MPTP can affect in vivo mitochondria function, we measured the activities of mitochondrial respiratory chain complexes in several tissues. Our results show that MPTP affects mainly mitochondrial respiratory chain complex IV, as found in Leigh Syndrome, confirming that acute MPTP intoxicated mice are a good model of Leigh Syndrome.

Some cases of maternally inherited isolated deafness are caused by mtDNA mutations, frequently following an exposure to aminoglycosides. Two mitochondrial genes have been clearly described as being affected by mutations responsible for this pathology: the ribosomal RNA 12S gene and the transfer RNA serine (UCN) gene. A previous study identified several candidate novel mtDNA mutations, localized in a variety of mitochondrial genes, found in patients with no previous treatment with aminoglycosides. Five of these candidate mutations are characterized in the present study. These mutations are localized in subunit ND1 of complex I of the respiratory chain (m.3388C>A [p.MT-ND1:Leu28Met]), the tRNA for Isoleucine (m.4295A>G), subunit COII of complex IV (m.8078G>A [p.MT-CO2:Val165Ile]), the tRNA of Serine 2 (AGU/C) (m.12236G>A), and Cytochrome B, subunit of complex III (m.15077G>A [p.MT-CYB:Glu111Lys]). Cybrid cell lines have been constructed for each of the studied mtDNA mutations and functional studies have been performed to assess the possible consequences of these mutations on mitochondrial bioenergetics. This study shows that a variety of mitochondrial genes, including protein-coding genes, can be responsible for nonsyndromic deafness, and that exposure to aminoglycosides is not required to develop the disease, giving new insights on the molecular bases of this pathology., (© 2012 Wiley Periodicals, Inc.)