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The article investigates the effects of bezafibrate on fatty-acid oxidation (FAO) capacities for very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficient genotypes from patient cells. Bezafibrate is found to improve the FAO defect in patient cells.

A report is presented on the exclusion of the leukemia inhibitory factor receptor gene in Crisponi syndrome and the identification of homozygote or compound heterozygote cytokine receptor-like factor 1 (CRLF1) mutations in four children from three unrelated families. The identification of CRLF 1 mutations in Crisponi syndrome supports the key role of the CNTFR pathway in the function of the autonomic nervous system.

A study was undertaken to analyze the physiological role of dietary lipids in regulating the abundance of long-term or short-term beta-oxidation enzyme mRNA in the developing kidney cortex and the inner stripe of the outer medulla (ISOM) in rats. It was hypothesized that the enzyme regulation involves the control of peroxisomal and mitochondrial beta-oxidation gene expression influenced by the binding of fatty acids to a nuclear receptor. Results revealed that alteration in the dietary lipid supply caused changes in the gene expression of enzymes in the cortex but not in the ISOM.

The kinetics and properties of Na-K-adenosine triphosphatase (ATPase) were analyzed by quantitative histochemical techniques in fetal rodent proximal tubules and neonatal rat kidney. Analysis of fetal rodent proximal tubules and neonatal rat kidney by enzymatic microassay indicated the presence of differentially high levels of Na-K-ATPase and mitochondrial oxidative enzymes compared to undifferentiated mesenchymal cells. Furthermore, mitochondrial enzymes and Na-K-ATPase mediate the turnover of ATP in the fetal rat proximal tubules.

The development regulation of two ketone body oxidative pathway enzymes by thyroid hormones was studied in rat proximal tubule. In 21-day-old hypothyroid pups, all mitochondrial enzyme activity except acetoacetyl-CoA decreased. Normal development was restored by treatment with triiodothyronine, which indicates it is important in triggering mitochondrial oxidative enzyme development.

Increases in respiratory chain (RC) enzyme activity, mitochondrial density and mitochondrial DNA levels are associated with mitochondrial biogenesis in the medullary thick ascending limb of Henle's loop (MTAL) in rat kidney. Glucocorticoids mediate RC enzyme activity and growth of inner mitochondrial membrane (IMM), and are not involved in mitochondrial DNA level and density changes. Ontogenic variations in MTAL cells influence kidney urine-dependent processes.

Focuses on the effect of thyroid hormones on the development of energy metabolism enzymes in rat proximal convoluted tubule (PCT). Animals and treatments; Analytical methods; Developmental patterns of mitochondrial oxidative enzymes in PCT; Compared development of oxidative enzymes in PCT of juxtamedullary and subcapsular nephrons.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrP C could be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNP gene encoding PrP C is associated with EMT. By manipulating the levels of PrP C in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrP C is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrP C operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrP C levels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNP levels increase with TKI resistance and that reducing PRNP expression sensitizes cells to osimertinib. Finally, we found that plasma PrP C levels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrP C as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrP C levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrP C -targeted therapies for EGFR-mutated NSCLC patients with TKI failure., (© 2024. The Author(s).)

Background: The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrP C , which represents a candidate therapeutic target. How PrP C is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrP C expression and to shed light on the gene regulatory networks linked to PrP C ., Methods: We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients., Results: In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrP C and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrP C , β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence., Conclusions: An unleashed PrP C -dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis., (© 2024. The Author(s).)

Background: Colorectal cancer (CRC) can be classified into four molecular subtypes (CMS) among which CMS1 is associated with the best prognosis, while CMS4, the mesenchymal subtype, has the worst outcome. Although mitochondria are considered to be hubs of numerous signaling pathways, the study of mitochondrial metabolism has been neglected for many years. Mitochondrial Complex I (CI) plays a dual role, both in energy and reactive oxygen species (ROS) production. However, the possible contribution of CI to tumorigenesis in cancer remains unclear. The purpose of this study was to investigate the CI under the prism of the CMS classification of CRC in ex vivo models., Methods: Biochemical dosages, bioenergetics analysis and western-blot were used to characterize CI expression, function and redox balance in LoVo and MDST8 cell lines, belonging to CMS1 and CMS4 subgroups, respectively. Cell proliferation and migration were assessed by xCELLigence technology. Overproduction or scavenging of mitochondrial ROS (mtROS) were performed to analyze the effect of mtROS on proliferation, migration, and mesenchymal markers. Focal adhesion kinase (FAK) and its activation were analyzed by immunofluorescence. We assessed the distribution of two CI scores in CRC cohorts according to CMS classification and their relevance for patient survival., Results: We found that CI is downregulated in CMS4 cells and is associated with elevated mtROS. We establish for the first time that in these migrating cells, mtROS production is maintained at optimal levels not only through changes in CI activity but also by inactivation/acetylation of superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. We show that promoting or scavenging mtROS both mitigate CMS4 cells' migration. Our results also point to a mtROS-mediated focal adhesion kinase (FAK) activation, which likely sustains their migratory phenotype. Using cohorts of CRC patients, we document that the expression of CI is downregulated in the CMS4 subgroup, and that low CI expression is associated with poor prognosis. Patients' datasets reveal an inverse correlation between CI and the epithelial-mesenchymal transition (EMT) pathway., Conclusion: We showed that inhibition of CI contributes to heighten mtROS, which likely foster MDST8 migration and might account for the specific EMT signature of CMS4 tumors. These data reveal a novel role of mitochondrial CI in CRC, with biological consequences that may be targeted with anti- or pro-oxidant drugs in clinical practice., (© 2023. The Author(s).)

The cellular prion protein PrP C partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrP C and CAV1 across cancer. Using cell-based assays, we show that PrP C regulates the expression of and interacts with CAV1. PrP C additionally controls the expression of the amyloid precursor protein APP and of the Aβ generating enzyme BACE1, and regulates the levels of Aβ, whose accumulation is a central event in Alzheimer's disease. We further identify DKK1 and DKK3, involved in both Alzheimer's disease and cancer progression, as targets of the PrP C -dependent axis. Finally, we establish that antibody-mediated blocking of the Aβ-PrP C interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aβ-PrP C -dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aβ-PrP C axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer., (© 2022. The Author(s).)

Objective: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health., Design: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1 H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes., Results: In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion., Conclusion: Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Corruption of cellular prion protein (PrPC) function(s) at the plasma membrane of neurons is at the root of prion diseases, such as Creutzfeldt-Jakob disease and its variant in humans, and Bovine Spongiform Encephalopathies, better known as mad cow disease, in cattle. The roles exerted by PrPC, however, remain poorly elucidated. With the perspective to grasp the molecular pathways of neurodegeneration occurring in prion diseases, and to identify therapeutic targets, achieving a better understanding of PrPC roles is a priority. Based on global approaches that compare the proteome and metabolome of the PrPC expressing 1C11 neuronal stem cell line to those of PrPnull-1C11 cells stably repressed for PrPC expression, we here unravel that PrPC contributes to the regulation of the energetic metabolism by orienting cells towards mitochondrial oxidative degradation of glucose. Through its coupling to cAMP/protein kinase A signaling, PrPC tones down the expression of the pyruvate dehydrogenase kinase 4 (PDK4). Such an event favors the transfer of pyruvate into mitochondria and its conversion into acetyl-CoA by the pyruvate dehydrogenase complex and, thereby, limits fatty acids β-oxidation and subsequent onset of oxidative stress conditions. The corruption of PrPC metabolic role by pathogenic prions PrPSc causes in the mouse hippocampus an imbalance between glucose oxidative degradation and fatty acids β-oxidation in a PDK4-dependent manner. The inhibition of PDK4 extends the survival of prion-infected mice, supporting that PrPSc-induced deregulation of PDK4 activity and subsequent metabolic derangements contribute to prion diseases. Our study posits PDK4 as a potential therapeutic target to fight against prion diseases., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: J.M.L has non-financial competing interests with Hoffmann La Roche Ltd laboratories. He acts as an expert witness for Hoffmann La Roche Ltd laboratories.