Mitochondrial Complex I Activity Is Required for Maximal Autophagy

Cells adapt to nutrient and energy deprivation by inducing autophagy, which is regulated by the mammalian target of rapamycin (mTOR) and AMP-activated protein kinases (AMPKs). We found that cell metabolism significantly influences the ability to induce autophagy, with mitochondrial complex I function being an important factor in the initiation, amplitude, and duration of the response. We show that phenformin or genetic defects in complex I suppressed autophagy induced by mTOR inhibitors, whereas autophagy was enhanced by strategies that increased mitochondrial metabolism. We report that mTOR inhibitors significantly increased select phospholipids and mitochondrial-associated membranes (MAMs) in a complex I-dependent manner. We attribute the complex I autophagy defect to the inability to increase MAMs, limiting phosphatidylserine decarboxylase (PISD) activity and mitochondrial phosphatidylethanolamine (mtPE), which support autophagy. Our data reveal the dynamic and metabolic regulation of autophagy

Effect of low doses of actinomycin D on neuroblastoma cell lines

Neuroblastoma is a malignant embryonal tumor occurring in young children, consisting of undifferentiated neuroectodermal cells derived from the neural crest. Current therapies for high-risk neuroblastoma are insufficient, resulting in high mortality rates and high incidence of relapse. With the intent to find new therapies for neuroblastomas, we investigated the efficacy of low-doses of actinomycin D, which at low concentrations preferentially inhibit RNA polymerase I-dependent rRNA trasncription and therefore, ribosome biogenesis. Neuroblastoma cell lines with different p53 genetic background were employed to determine the response on cell viability and apoptosis of low-dose of actinomycin D. Subcutaneously-implanted SK-N-JD derived neuroblastoma tumors were used to assess the effect of low-doses of actinomycin D on tumor formation. Low-dose actinomycin D treatment causes a reduction of cell viability in neuroblastoma cell lines and that this effect is stronger in cells that are wild-type for p53. MYCN overexpression contributes to enhance this effect, confirming the importance of this oncogene in ribosome biogenesis. In the wild-type SK-N-JD cell line, apoptosis was the major mechanism responsible for the reduction in viability and we demonstrate that treatment with the MDM2 inhibitor Nutlin-3, had a similar effect to that of actinomycin D. Apoptosis was also detected in p53 −/− deficient LA1-55n cells treated with actinomycin D, however, only a small recovery of cell viability was found when apoptosis was inhibited by a pan-caspase inhibitor, suggesting that the treatment could activate an apoptosis-independent cell death pathway in these cells. We also determined whether actinomycin D could increase the efficacy of the histone deacetylase inhibitor, SAHA, which is in being used in neuroblastoma clinical trials. We show that actinomycin D synergizes with SAHA in neuroblastoma cell lines. Moreover, on subcutaneously-implanted neuroblastoma tumors derived from SK-N-JD cells, actinomycin D led to tumor regression, an effect enhanced in combination with SAHA. The results presented in this work demonstrate that actinomycin D, at low concentrations, inhibits proliferation and induces cell death in vitro, as well as tumor regression in vivo. From this study, we propose that use of ribosome biogenesis inhibitors should be clinically considered as a potential therapy to treat neuroblastomas. The online version of this article (doi:10.1186/s12943-015-0489-8) contains supplementary material, which is available to authorized users

Neuropeptide precursor VGF is genetically associated with social anhedonia and underrepresented in the brain of major mental illness: its downregulation by DISC1

In a large Scottish pedigree, disruption of the gene coding for DISC1 clearly segregates with major depression, schizophrenia and related mental conditions. Thus, study of DISC1 may provide a clue to understand the biology of major mental illness. A neuropeptide precursor VGF has potent antidepressant effects and has been reportedly associated with bipolar disorder. Here we show that DISC1 knockdown leads to a reduction of VGF, in neurons. VGF is also downregulated in the cortices from sporadic cases with major mental disease. A positive correlation of VGF single-nucleotide polymorphisms (SNPs) with social anhedonia was also observed. We now propose that VGF participates in a common pathophysiology of major mental disease

Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease

Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with nonalcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease

A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis

The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks

Physical activity as a preventive measure against overweight, obesity, infections, allergies and cardiovascular disease risk factors in adolescents: AFINOS Study protocol

<p>Abstract</p> <p>Background</p> <p>Prior studies addressing the impacts of regular physical activity or sedentary habits on the immune system have been conducted in adults and laboratory settings. Thus, it is practically unknown how a healthy active lifestyle could affect low-grade inflammation processes, infections or allergies in young persons. The AFINOS Study was designed to determine the relationship between the regular physical activity levels of adolescents and overweight, infection, and allergies along with the presence of metabolic and immunological biomarkers of a deteriorated health status. A further objective of the AFINOS Study is to assess the health status and lifestyle habits of an adolescent population in an effort to identify any protective factors that could be used as preventive measures, since many chronic diseases and their associated co-morbidities often persist from adolescence into adulthood.</p> <p>Methods/Design</p> <p>This study was conducted as three separate sub-studies in three different populations as follows: (a) Study 1 was performed on a population sample of adolescents; (b) Study 2 on the adolescents' parents; and (c) Study 3 on a subset of the adolescents from Study 1. Study 1 assessed health and lifestyle indicators through a questionnaire administered to a representative sample of adolescents from the Madrid Region (n = 2400) aged 13 to 16 years. In Study 2, the parents of the teenagers participating in Study 1 were required to fill out a questionnaire. Finally in Study 3, body composition, physical activity, health-related physical fitness, and blood measurements were determined in a subset (n = 200) of the individuals included in Study 1.</p> <p>Discussion</p> <p>This paper describes the rationale, design, and methodologies used in the AFINOS Study. This multidisciplinary, multicenter study seeks to evaluate several aspects of existing relationships between routine physical activity/sedentary behaviour and several health status markers, specifically those related to the immune system. The results of this cross-sectional study will serve for comparisons with the available data obtained in laboratory settings and in adults. In addition, knowledge regarding the health status and lifestyle habits of Spanish adolescents and their parents will be useful for designing preventive measures.</p

Excessive TV viewing and cardiovascular disease risk factors in adolescents. The AVENA cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Excessive television (TV) viewing might play an important role in the development of cardiovascular disease (CVD). The aim of this study was to examine the independent associations between TV viewing and CVD risk factors in adolescents.</p> <p>Methods</p> <p>A sample of 425 adolescents, aged 13- to 18.5-year-old, was included in this study. Body mass index (BMI), waist circumference (WC), glucose, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, apolipoprotein (apo) A-1, apo B-100, and lipoprotein(a) levels were determined. A composite CVD risk score was computed based on age-, sex-, sexual maturation- and race-standardized triglycerides, HDL-cholesterol, LDL-cholesterol and glucose. TV viewing was self-reported.</p> <p>Results</p> <p>Two hundred and twenty-five adolescents (53%) who spent >3 hrs/day watching TV were considered as the "high TV viewing" group. Ninety-nine adolescents (23%) from the total sample were classified as overweight according to International age- and sex-specific BMI values. The high TV viewing group had significantly less favorable values of HDL-cholesterol, glucose, apo A1 and CVD score, independent of age, sex, sexual maturation, race and weight status. There was a significant interaction effect of TV viewing × weight status (P = 0.002) on WC, and the negative influence of TV viewing on WC persisted in the overweight group (P = 0.031) but was attenuated in non-overweight adolescents (P > 0.05).</p> <p>Conclusion</p> <p>Excessive TV viewing seems to be related to an unfavorable CVD risk factors profile in adolescence. Reducing TV viewing in overweight adolescents might be beneficial to decrease abdominal body fat.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe