mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1.

The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/fusion, ATP production, metabolite biogenesis, and apoptosis, are not well understood. Here, we demonstrate that the nutrient-sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin-related protein 1 (DRP1). Potent active-site mTOR inhibitors engender mitochondrial hyperfusion due to the diminished translation of MTFP1, which is mediated by translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for cell survival upon mTOR inhibition through mitochondrial hyperfusion employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions.

Access to general practice during the COVID-19 pandemic - a cross-sectional view of the opinions of adults who use social media.

INTRODUCTION: The COVID-19 pandemic has had a significant impact on the health and wellbeing of people worldwide. General practices were forced to adapt to constantly changing circumstances, leading to predominance of virtual consultations. The aim of this study was to examine the impact the pandemic had on the ability of patients to access general practice. Other focuses included determining the nature of changes to appointment cancellations or delays and the level of disruption to long-term medication regimes during this period. METHODS: A 25-question online survey was administered using Qualtrics®. Adult patients of Irish general practices were recruited via social media between October 2020 and February 2021. The data were examined for associations between participant groupings and key findings using chi-squared tests. RESULTS: 670 persons participated. Half of all doctor-patient consultations during that time were completed virtually, predominantly via telephone. Overall, 497 (78%) participants accessed their healthcare teams as scheduled, and without disruption. 18% of participants (n=104) reported difficulty in accessing their long-term medications; those who were younger, and those who typically attend general practice on a quarterly or more basis, were associated most with this disruption (p<0.05; p<0.05). DISCUSSION: Despite the COVID-19 pandemic, Irish general practice has maintained its schedule for appointments in greater than three quarters of cases. There was a clear shift away from face-to-face consultations to telephone appointments. Maintaining the prescription of long-term medications for patients remains a challenge. Further work needs to be done to ensure the continuation of care and undisrupted medication schedules during any future pandemics.

Access to general practice during COVID-19: a cross-sectional view of the opinions of adults who use social media.

Background/Aim: Since the onset of the COVID-19 pandemic, virtual consultations have become commonplace, and access to healthcare more complex. The study was designed to examine the impact COVID-19 has had on access to general practice care in Ireland. Methods: A 25-question online survey was designed in Qualtrics®. Adult patients of Irish general practices were recruited via social media between October 2020 and February 2021 and volunteered their opinions. Results: 670 persons participated. Half of all doctor-patient consultations were now completed virtually-predominantly via telephone. Overall, 497 (78%) participants accessed their healthcare teams as scheduled, and without disruption. 18% of participants (n=104) reported difficulty in accessing their long-term medications; those who are younger, and those who typically attend general practice quarterly or more, were associated most with this disruption (p<0.05). Fifty-nine instances where a new health concern was subject to an appointment cancellation or rescheduling were reported. Conclusions: Despite the COVID-19 pandemic, Irish general practice has maintained its schedule for appointments in 78% of cases despite the challenges of the pandemic. Half of consultations were provided virtually; teleconsultation use was very infrequent. Maintaining the supply chain for long-term medications for patients remains a challenge during a pandemic. Authors accept that study participants were confined to those who use social media. A protocol may need to be designed by each practice to optimize the continuation of care and of medication schedules during any future pandemics.

4E-BP-Dependent Translational Control of Irf8 Mediates Adipose Tissue Macrophage Inflammatory Response.

Deregulation of mRNA translation engenders many human disorders, including obesity, neurodegenerative diseases, and cancer, and is associated with pathogen infections. The role of eIF4E-dependent translational control in macrophage inflammatory responses in vivo is largely unexplored. In this study, we investigated the involvement of the translation inhibitors eIF4E-binding proteins (4E-BPs) in the regulation of macrophage inflammatory responses in vitro and in vivo. We show that the lack of 4E-BPs exacerbates inflammatory polarization of bone marrow-derived macrophages and that 4E-BP-null adipose tissue macrophages display enhanced inflammatory gene expression following exposure to a high-fat diet (HFD). The exaggerated inflammatory response in HFD-fed 4E-BP-null mice coincides with significantly higher weight gain, higher Irf8 mRNA translation, and increased expression of IRF8 in adipose tissue compared with wild-type mice. Thus, 4E-BP-dependent translational control limits, in part, the proinflammatory response during HFD. These data underscore the activity of the 4E-BP-IRF8 axis as a paramount regulatory mechanism of proinflammatory responses in adipose tissue macrophages.

Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis.

Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2.

Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-ß (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tract-binding protein 1 (PTBP1) promotes the retention of an intron in the 5'-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.