Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression

Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression

The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage

The metabolic plasticity of mitochondria ensures cell development, differentiation, and survival. The peptidase OMA1 regulates mitochondrial morphology via OPA1 and stress signaling via DELE1 and orchestrates tumorigenesis and cell survival in a cell- and tissue-specific manner. Here, we use unbiased systems-based approaches to show that OMA1-dependent cell survival depends on metabolic cues. A metabolism-focused CRISPR screen combined with an integrated analysis of human gene expression data found that OMA1 protects against DNA damage. Nucleotide deficiencies induced by chemotherapeutic agents promote p53-dependent apoptosis of cells lacking OMA1. The protective effect of OMA1 does not depend on OMA1 activation or OMA1-mediated OPA1 and DELE1 processing. OMA1-deficient cells show reduced glycolysis and accumulate oxidative phosphorylation (OXPHOS) proteins upon DNA damage. OXPHOS inhibition restores glycolysis and confers resistance against DNA damage. Thus, OMA1 dictates the balance between cell death and survival through the control of glucose metabolism, shedding light on its role in cancerogenesis

Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

19 Páginas.-- 7 FigurasATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.This work was funded by grants from the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, co-funded by Fondos FEDER (PI15/00134, PI18/01590, CPII19/00023 to A.M.M.) and the Ministerio de Ciencia e Innovación (PID2021-123965OB-100 to A.M.M.). A.M.M. is funded by the Junta de Andalucía P20_00480, the Spanish Society of Diabetes, and CSIC 202220I059. M.S.K. is funded by the Nordea Foundation (#02-2017-1749), the Novo Nordisk Foundation (#NNF17OC0027812), the Neye Foundation, the Lundbeck Foundation (#R324-2019-1492), the Ministry of Higher Education and Science of Denmark (#0238-00003B). V.C.G. is funded by the Instituto de Salud Carlos III (CP19/00046), co-funded by FEDER. F.M. is funded by the CIBERDEM of the Instituto de Salud Carlos III. A.M.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We acknowledge the support of the group of basic research on diabetes of the Spanish Society of Diabetes.Peer reviewe

Understanding the effects of thyroxine supplementation to explore novel venues for the treatment of type 2 diabetes mellitus

Resumen del póster presentado al XXVIII Congreso Nacional de la Sociedad Española de diabetes, celebrado en Bilbao del 20 al 22 de abril de 2016.[Introduction and objectives]: Thyroid hormone (T4) supplementation is known to increase glucose utilization in insulin-target tissues yet patients suffering from hyperthyroidism develop long term metabolic disorders that are, in certain cases, associated with type 2 diabetes mellitus (T2DM). Herein we sought to understand the underlying mechanism of this dichotomy with the goal to target thyroid hormone signalling pathways beneficial for the treatment of T2DM. [Material and methods]: Newborn C57/Bl6 mice were treated with T4 until the age of 32 weeks. Body weight was monitored monthly and physical performance was evaluated by rotarod test. Percentage of glycated haemoglobin (HbA1c), oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and glucose quantifications during a 24 hours fasting test were determined to assess metabolic homeostasis. Prior to sacrifice at 32 weeks of age, mice were either injected with insulin (1.5 IU.Kg-1) or saline solution. Protein extracts were then prepared from skeletal muscles and total protein levels for AKT, GSK3β and FOXO1 as well as AKT phosphorylation, implicated in insulin signaling, were assessed by Western blot analysis. [Results]: T4-treated mice exhibited a 12-34% lower body weight during the course of the study and displayed improved physical performance. Mice exposed to exogenous T4 showed lower circulating glucose in OGTT (30%), and ITT (37%) as compared to untreated animals, suggesting enhanced glucose clearance. Consistent with the latter, the percentage of HbA1c was reduced in T4-treated mice. Total AKT, GSK3β and FOXO1 protein levels were higher in skeletal muscles of T4-treated mice as compared to untreated mice under basal conditions (e.g. non-insulin treated). Interestingly, increased AKT phosphorylation (Serine 473) was also detected in non-insulin treated T4-supplemented mice. Insulin injection induced maximal AKT phosphorylation in both control and T4-treated mice. [Conclusions]: Our data suggest that T4 supplementation enhances skeletal muscle glucose uptake under basal conditions through increased AKT phosphorylation, resulting in improved metabolic homeostasis and physical performance, while reducing body weight gain. We propose that, although hyperthyroidism is a serious disease that prevents the use of T4 in the clinic, interventions based on the modulation of T4-targets may be a promising strategy for the development of novel therapies for the treatment of T2DM.Peer reviewe

Understanding the effects of thyroxine supplementation to explore novel venues for the treatment of type 2 diabetes mellitus

Resumen del póster presentado al XXVIII Congreso Nacional de la Sociedad Española de diabetes, celebrado en Bilbao del 20 al 22 de abril de 2016.[Introduction and objectives]: Thyroid hormone (T4) supplementation is known to increase glucose utilization in insulin-target tissues yet patients suffering from hyperthyroidism develop long term metabolic disorders that are, in certain cases, associated with type 2 diabetes mellitus (T2DM). Herein we sought to understand the underlying mechanism of this dichotomy with the goal to target thyroid hormone signalling pathways beneficial for the treatment of T2DM. [Material and methods]: Newborn C57/Bl6 mice were treated with T4 until the age of 32 weeks. Body weight was monitored monthly and physical performance was evaluated by rotarod test. Percentage of glycated haemoglobin (HbA1c), oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and glucose quantifications during a 24 hours fasting test were determined to assess metabolic homeostasis. Prior to sacrifice at 32 weeks of age, mice were either injected with insulin (1.5 IU.Kg-1) or saline solution. Protein extracts were then prepared from skeletal muscles and total protein levels for AKT, GSK3β and FOXO1 as well as AKT phosphorylation, implicated in insulin signaling, were assessed by Western blot analysis. [Results]: T4-treated mice exhibited a 12-34% lower body weight during the course of the study and displayed improved physical performance. Mice exposed to exogenous T4 showed lower circulating glucose in OGTT (30%), and ITT (37%) as compared to untreated animals, suggesting enhanced glucose clearance. Consistent with the latter, the percentage of HbA1c was reduced in T4-treated mice. Total AKT, GSK3β and FOXO1 protein levels were higher in skeletal muscles of T4-treated mice as compared to untreated mice under basal conditions (e.g. non-insulin treated). Interestingly, increased AKT phosphorylation (Serine 473) was also detected in non-insulin treated T4-supplemented mice. Insulin injection induced maximal AKT phosphorylation in both control and T4-treated mice. [Conclusions]: Our data suggest that T4 supplementation enhances skeletal muscle glucose uptake under basal conditions through increased AKT phosphorylation, resulting in improved metabolic homeostasis and physical performance, while reducing body weight gain. We propose that, although hyperthyroidism is a serious disease that prevents the use of T4 in the clinic, interventions based on the modulation of T4-targets may be a promising strategy for the development of novel therapies for the treatment of T2DM.Peer reviewe