Cellular Energy Demand Research Articles

Isomeric lipid signatures reveal compartmentalized fatty acid metabolism in cancer

The cellular energy and biomass demands of cancer drive a complex dynamic between uptake of extracellular FAs and their de novo synthesis. Given that oxidation of de novo synthesized FAs for energy would result in net-energy loss, there is an implication that FAs from these two sources must have distinct metabolic fates; however, hitherto, all FAs have been considered part of a common pool. To probe potential metabolic partitioning of cellular FAs, cancer cells were supplemented with stable isotope-labeled FAs. Structural analysis of the resulting glycerophospholipids revealed that labeled FAs from uptake were largely incorporated to canonical (sn-) positions on the glycerol backbone. Surprisingly, labeled FA uptake also disrupted canonical isomer patterns of the unlabeled lipidome and induced repartitioning of n-3 and n-6 PUFAs into glycerophospholipid classes. These structural changes support the existence of differences in the metabolic fates of FAs derived from uptake or de novo sources and demonstrate unique signaling and remodeling behaviors usually hidden from conventional lipidomics.

Real Time Imaging of Mitochondrial Dynamics in the Dorsal Root Ganglion Following Nerve Injury

Mitochondria are dynamic and motile organelles that respond rapidly to oxidative stress and cellular energy demands. Their morphological changes, as determined by fission and fusion, have been linked to the progression of neuropathic pain. However, little is known about specific pathology underlying mitochondrial dysfunction after peripheral nerve injury or how pharmacological interventions affect these changes. Our goal is to evaluate mitochondrial dynamics following peripheral nerve injury by characterizing axonal mitochondrial density, movement in axons and fusion-fission events. We dissociated dorsal root ganglia (DRG) from mice with spare nerve injury (SNI) and selectively labelled mitochondria with a live-cell fluorescent dye. Time lapse videos were then captured using a spinning disk confocal microscope. We observed a significant increase in axonal mitochondrial density in DRG cultures obtained from SNI mice when compared to naïve cultures. Representative kymograph images depict a larger proportion of mitochondria moving anterogradely in axons of DRG neurons from SNI mice. Interestingly, we found that the SNI-mitochondria are trafficked at lower velocities. Previous studies have shown that calcium overload in damaged mitochondria may contribute to decreased mitochondrial motility. Additionally, we observe a decrease in perinuclear clustering within the SNI group which may indicate a disruption in mitochondrial networking or a failure to regulate fission events in DRG neurons after injury. Collectively, our findings highlight the benefit of real time imaging of DRG neurons to gain greater insight into specific aspects of mitochondrial dysfunction after nerve injury. Our findings likely have important implications for therapeutic approaches to neuropathic pain. Supported by NIH grant NS065926.

Biophysical mechanisms of condition-dependent mRNA localization to the mitochondria

Mitochondria are dynamic organelles that must precisely control their protein composition according to cellular energy demand. One way in which gene expression can be modulated post-transcriptionally is through localization of nuclear-encoded mRNAs to the mitochondrial surface. As yeast switch to respiratory metabolism, there is an increase in the fraction of the cytoplasm that is mitochondrial. Our data point to this change in mitochondrial volume fraction increasing the localization of certain nuclear-encoded mRNAs to the surface of the mitochondria.

Rapid and Direct Action of Lipopolysaccharide (LPS) on Skeletal Muscle of Larval Drosophila.

Simple SummaryThe direct action of a toxin, lipopolysaccharide, which is released from bacteria, on tissues is still not well understood. Skeletal muscle exposed to lipopolysaccharide in the larvae of the fruit fly (Drosophila melanogaster) causes the membrane potential to become more negative. The mechanism for this change was investigated in this study. It appears this may be due to a potassium ion leaving the cell, and this response is independent of calcium ions flowing into the cell. The endotoxin lipopolysaccharide (LPS) from Gram-negative bacteria exerts a direct and rapid effect on tissues. While most attention is given to the downstream actions of the immune system in response to LPS, this study focuses on the direct actions of LPS on skeletal muscle in Drosophila melanogaster. It was noted in earlier studies that the membrane potential rapidly hyperpolarizes in a dose-dependent manner with exposure to LPS from Pseudomonas aeruginosa and Serratia marcescens. The response is transitory while exposed to LPS, and the effect does not appear to be due to calcium-activated potassium channels, activated nitric oxide synthase (NOS), or the opening of Cl− channels. The purpose of this study was to further investigate the mechanism of the hyperpolarization of the larval Drosophila muscle due to exposure of LPS using several different experimental paradigms. It appears this response is unlikely related to activation of the Na-K pump or Ca2+ influx. The unknown activation of a K+ efflux could be responsible. This will be an important factor to consider in treatments of bacterial septicemia and cellular energy demands.

Mitochondrial Bioenergetic and Proteomic Phenotyping Reveals Organ-Specific Consequences of Chronic Kidney Disease in Mice.

Chronic kidney disease (CKD) results in reduced kidney function, uremia, and accumulation of uremic metabolites. Mitochondrial alterations have been suggested to play a role in the disease pathology within various tissues. The purpose of this study was to perform a comprehensive bioenergetic and proteomic phenotyping of mitochondria from skeletal muscle (SkM), cardiac muscle (CM), and renal tissue from mice with CKD. The 5-month-old C57BL/6J male mice were fed a casein control or adenine-supplemented diet for 6 months. CKD was confirmed by blood urea nitrogen. A mitochondrial diagnostic workflow was employed to examine respiratory function, membrane and redox potential, reactive oxygen species production, and maximal activities of matrix dehydrogenases and electron transport system (ETS) protein complexes. Additionally, tandem-mass-tag-assisted proteomic analyses were performed to uncover possible differences in mitochondrial protein abundance. CKD negatively impacted mitochondrial energy transduction (all p < 0.05) in SkM, CM, and renal mitochondria, when assessed at physiologically relevant cellular energy demands (ΔGATP) and revealed the tissue-specific impact of CKD on mitochondrial health. Proteomic analyses indicated significant abundance changes in CM and renal mitochondria (115 and 164 proteins, p < 0.05), but no differences in SkM. Taken together, these findings reveal the tissue-specific impact of chronic renal insufficiency on mitochondrial health.

MCU-complex-mediated mitochondrial calcium signaling is impaired in Barth syndrome.

Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like Barth syndrome (BTHS) is not known. Here we utilized multiple models of BTHS including yeast, mouse muscle cell line, as well as BTHS patient cells and cardiac tissue to show that CL is required for the abundance and stability of the MCU-complex regulatory subunit MICU1. Interestingly, the reduction in MICU1 abundance in BTHS mitochondria is independent of MCU. Unlike MCU and MICU1/MICU2, other subunit and associated factor of the uniporter complex, EMRE and MCUR1, respectively, are not affected in BTHS models. Consistent with the decrease in MICU1 levels, we show that the kinetics of MICU1-dependent mitochondrial calcium uptake is perturbed and acute stimulation of mitochondrial calcium signaling in BTHS myoblasts fails to activate pyruvate dehydrogenase, which in turn impairs the generation of reducing equivalents and blunts mitochondrial bioenergetics. Taken together, our findings suggest that defects in mitochondrial calcium signaling could contribute to cardiac and skeletal muscle pathologies observed in BTHS patients.

Abstract P430: VSMCs Increase Glutamine Utilization For Energy Metabolism During Obesity

Obesity increases the risk of developing cardiovascular disease through vascular remodeling though the underlying mechanisms are not entirely understood. However, metabolic fuel partitioning and mitochondrial flexibility during energy metabolism may play a critical role. We demonstrated serum and glucocorticoid-inducible kinase 1 (SGK-1) is up-regulated in the vasculature of diet-induced obese mice and that SGK-1 deletion is protective against obesity-induced vascular remodeling by metabolically reprogramming vascular smooth muscle cell (VSMC) energy metabolism towards oxidative phosphorylation (OXPHOS) and away from glycolysis. Mitochondrial substrate availability and utilization of the primary metabolic fuels glucose, long chain fatty acids (LCFAs) and glutamine can drive metabolic reprogramming. Therefore, alterations in fuel utilization may contribute to vascular remodeling during obesity. The purpose of this study was to examine SGK-1’s role in 1) fuel dependency: a cell’s reliance for a specific fuel and 2) fuel capacity: a cell’s ability to oxidize a specific fuel to meet cellular energy demand under low-fat and high-fat diet-induced obesity. Using the MitoXpress Oxygen Consumption assay which measures OXPHOS, primary VSMCs isolated from wildtype (WT) and SMC-specific SGK-1 knockout (smSGK-1 KO) mice fed a 10% kcal low-fat or 45% kcal high-fat diet for eight weeks were seeded in a 96-well plate at a density of 6x10 4 cells/well in culture medium. To assess fuel dependency, cells were treated with fuel pathway inhibitors UK5099, Etomoxir or BPTES to block glucose, LCFA or glutamine oxidation, respectively. To measure fuel capacity, VSMCs were treated with a combination of two pathway inhibitors simultaneously. Next, samples were overlaid with a fluorescent extracellular oxygen consumption reagent, sealed with high-sensitivity mineral oil, then signals were read at 1.5-minute intervals for 2 hours at Ex/Em= 380/650 nm. Our results show WT VSMCs are exclusively glucose-dependent for OXPHOS regardless of dietary conditions. However, SGK-1 deletion induces a dependency for all three fuels for OXPHOS in VSMCs under low- and high-fat conditions. Even though WT and smSGK-1 KO VSMCs preferentially oxidized glucose for OXPHOS under low-fat conditions; SGK-1 deletion resulted in a 2.2-fold increase in glutamine capacity. Alternatively, WT VSMCs exposed to obesogenic conditions preferentially oxidized glutamine whereas SGK-1 deletion induced a nearly equal partitioning of all three fuels during obesity suggesting elevated mitochondrial flexibility. Overall, this study suggests SGK-1 increases glucose dependency for energy metabolism under physiological and obesogenic conditions. Also, increased glutamine utilization for OXPHOS during obesity may be an underlying cause of VSMC dysfunction and subsequent vascular impairment.

The Effect of Microplastics on the Bioenergetics of the Mussel Mytilus coruscus Assessed by Cellular Energy Allocation Approach

Marine microplastics pollution is a major environmental concern in marine ecosystems worldwide, yet the biological impacts of microplastics on the coastal biota are not yet fully understood. We investigated the impact of suspended microplastics on the energy budget of the mussels Mytilus coruscus using the Cellular Energy Allocation (CEA) approach. The mussels were exposed to control conditions (no microplastics) or to one of the three concentrations of 2 μm polystyrene microspheres (10, 104, and 106 particles/L) for 14 days, followed by 7 days of recovery. Exposure to high concentrations of microplastics (104 or 106 particles/L) increased cellular energy demand (measured as the activity of the mitochondrial electron transport system, ETS) and depleted cellular energy stores (carbohydrates, lipids, and proteins) in the mussels whereas exposure to 10 particles/L had no effect. Carbohydrate levels decreased already after 7 days of microplastics exposure and were restored after 7 days of recovery. In contrast, the tissue levels of lipids and proteins declined more slowly (after 14 days of exposure) and did not fully recover after 7 days following the removal of microplastics. Therefore, the total energy content and the CEA declined after 7–14 days of exposure to high microplastics concentrations, and remained suppressed during 7 days of subsequent recovery. These findings demonstrate a negative impact of microplastics on energy metabolism at the cellular level that cannot be restored during a short time recovery. Given a close link of CEA with the organismal energy balance, suppression of CEA by microplastics exposure suggests that bioenergetics disturbances might lead to decreases in growth and productivity of mussels’ populations in environments with heavy microplastics loads.

WNT5B promotes vascular smooth muscle cell dedifferentiation via mitochondrial dynamics regulation in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by proliferative vascular remodeling. Abnormal vascular smooth muscle cell (VSMC) phenotype switching is crucial to this process, highlighting the need for VSMC metabolic changes to cover cellular energy demand in CTEPH. We report that elevated Wnt family member 5B (WNT5B) expression is associated with vascular remodeling and promotes VSMC phenotype switching via mitochondrial dynamics regulation in CTEPH. Using primary culture of pulmonary artery smooth muscle cells, we show that high WNT5B expression activates VSMC proliferation and migration and results in mitochondrial fission via noncanonical Wnt signaling in CTEPH. Abnormal VSMC proliferation and migration were abolished by mitochondrial division inhibitor 1, an inhibitor of mitochondrial fission. Secreted frizzled-related protein 2, a soluble scavenger of Wnt signaling, attenuates VSMC proliferation and migration by accelerating mitochondrial fusion. These findings indicate that WNT5B is an essential regulator of mitochondrial dynamics, contributing to VSMC phenotype switching in CTEPH.

Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous, debilitating, and complex disease. Along with disabling fatigue, ME/CFS presents an array of other core symptoms, including autonomic nervous system (ANS) dysfunction, sustained inflammation, altered energy metabolism, and mitochondrial dysfunction. Here, we evaluated patients’ symptomatology and the mitochondrial metabolic parameters in peripheral blood mononuclear cells (PBMCs) and plasma from a clinically well-characterised cohort of six ME/CFS patients compared to age- and gender-matched controls. We performed a comprehensive cellular assessment using bioenergetics (extracellular flux analysis) and protein profiles (quantitative mass spectrometry-based proteomics) together with self-reported symptom measures of fatigue, ANS dysfunction, and overall physical and mental well-being. This ME/CFS cohort presented with severe fatigue, which correlated with the severity of ANS dysfunction and overall physical well-being. PBMCs from ME/CFS patients showed significantly lower mitochondrial coupling efficiency. They exhibited proteome alterations, including altered mitochondrial metabolism, centred on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels. Overall, these results indicate that PBMCs from ME/CFS patients have a decreased ability to fulfill their cellular energy demands.

277-OR: Use of Noncarbohydrate Fuels Is Associated with Materno-Fetal Complications in Type 1 Diabetes Pregnancy: Metabolomics Analysis of the CONCEPTT Trial

Aims: We assessed metabolomic signatures in maternal and cord blood associated with suboptimal outcomes in the continuous glucose monitoring in women with type 1 diabetes in pregnancy trial (CONCEPTT). Methods: Serum samples from 162 mothers (12, 24 and 34 weeks’ gestation) and 93 cord blood samples were analysed for 1049 metabolites and 1041 lipids using ultra-performance liquid chromatography-tandem mass spectroscopy. We used adjusted and unadjusted logistic regression of metabolomic variables using adjudicated outcomes: extremely-large-for-gestational-age (ELGA; &amp;gt;97.5th centile), pre-eclampsia and neonatal hypoglycaemia with modified Bonferroni false discovery rate p≤0.001. Results: All materno-fetal complications studied were associated with reliance on non-carbohydrate sources of fuel. Lipids through beta oxidation were the main fuel source in ELGA (24 and 34 weeks), neonatal hypoglycaemia (12 weeks only) and pre-eclampsia (12 and 24 weeks). Marked protein catabolism was evident in neonatal hypoglycaemia (34 weeks) and pre-eclampsia (24 and 34 weeks). Cord blood in ELGA infants showed evidence of simultaneous beta oxidation and de novo lipogenesis, a biologically futile cycle of creating and destroying lipids, which consumes excess energy and substrate. Cord blood from infants with neonatal hypoglycaemia showed evidence of pronounced protein catabolism providing glucogenic amino acids for gluconeogenesis. Conclusions: Reliance on lipid or protein sources for fuel was associated with ELGA, neonatal hypoglycaemia and pre-eclampsia. Carbohydrate metabolism was insufficient to meet cellular energy demands, possibly due to insufficient insulin, insufficient dietary carbohydrate or both. Improving outcomes in type 1 diabetes pregnancy may require greater focus on normalising carbohydrate metabolism through optimal carbohydrate intake and matched insulin dosing. Disclosure C. L. Meek: None. Z. Stewart: None. S. Furse: None. J. M. Yamamoto: None. D. Feig: Advisory Panel; Self; Novo Nordisk. A. Koulman: None. H. R. Murphy: None. Funding JDRF (17/2011/533, 80/2010/585); Diabetes UK (DUK-HKF 17/0005712, DUK-PG 17/0005633.BBSRC BB/M027252/1)

Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis.

Mitochondria are highly dynamic, maternally inherited cytoplasmic organelles, which fulfill cellular energy demand through the oxidative phosphorylation system. Besides, they play an active role in calcium and damage-associated molecular patterns signaling, amino acid, and lipid metabolism, and apoptosis. Thus, the maintenance of mitochondrial integrity and homeostasis is extremely critical, which is achieved through continual fusion and fission. Mitochondrial fusion allows the transfer of gene products between mitochondria for optimal functioning, especially under metabolic and environmental stress. On the other hand, fission is crucial for mitochondrial division and quality control. The imbalance between these two processes is associated with various ailments such as cancer, neurodegenerative and cardiovascular diseases. This review discusses the molecular mechanisms that control mitochondrial fusion and fission and how the disruption of mitochondrial dynamics manifests into various disease conditions.

Mitochondrial remodelling-a vicious cycle in diabetic complications.

Diabetes mellitus (DM) is a chronic, metabolic condition characterized by excessive blood glucose that causes perturbations in physiological functioning of almost all the organs of human body. This devastating metabolic disease has its implications in cognitive decline, heart damage, renal, retinal and neuronal complications that severely affects quality of life and associated with decreased life expectancy. Mitochondria possess adaptive mechanisms to meet the cellular energy demand and combat cellular stress. In recent years mitochondrial homeostasis has been point of focus where several mechanisms regulating mitochondrial health and function are evaluated. Mitochondrial dynamics plays crucial role in maintaining healthy mitochondria in cell under physiological as well as stress condition. Mitochondrial dynamics and corresponding regulating mechanisms have been implicated in progression of metabolic disorders including diabetes and its complications. In current review we have discussed about role of mitochondrial dynamics under physiological and pathological conditions. Also, modulation of mitochondrial fission and fusion in diabetic complications are described. The available literature supports mitochondrial remodelling as reliable target for diabetic complications.

CpG-ODN induced antimicrobial immunity in neonatal chicks involves a substantial shift in serum metabolic profiles

Synthetic CpG-ODNs can promote antimicrobial immunity in neonatal chicks by enriching immune compartments and activating immune cells. Activated immune cells undergo profound metabolic changes to meet cellular biosynthesis and energy demands and facilitate the signaling processes. We hypothesize that CpG-ODNs induced immune activation can change the host’s metabolic demands in neonatal chicks. Here, we used NMR-based metabolomics to explore the potential of immuno-metabolic interactions in the orchestration of CpG-ODN-induced antimicrobial immunity. We administered CpG-ODNs to day-old broiler chicks via intrapulmonary (IPL) and intramuscular (IM) routes. A negative control group was administered IPL distilled water (DW). In each group (n = 60), chicks (n = 40) were challenged with a lethal dose of Escherichia coli, two days post-CpG-ODN administration. CpG-ODN administered chicks had significantly higher survival (P < 0.05), significantly lower cumulative clinical scores (P < 0.05), and lower bacterial loads (P < 0.05) compared to the DW control group. In parallel experiments, we compared NMR-based serum metabolomic profiles in neonatal chicks (n = 20/group, 24 h post-treatment) treated with IM versus IPL CpG-ODNs or distilled water (DW) control. Serum metabolomics revealed that IM administration of CpG-ODN resulted in a highly significant and consistent decrease in amino acids, purines, betaine, choline, acetate, and a slight decrease in glucose. IPL CpG-ODN treatment resulted in a similar decrease in purines and choline but less extensive decrease in amino acids, a stronger decrease in acetate, and a considerable increase in 2-hydroxybutyrate, 3-hydroxybutyrate, formic acid and a mild increase in TCA cycle intermediates (all P < 0.05 after FDR adjustment). These perturbations in pathways associated with energy production, amino acid metabolism and nucleotide synthesis, most probably reflect increased uptake of nutrients to the cells, to support cell proliferation triggered by the innate immune response. Our study revealed for the first time that CpG-ODNs change the metabolomic landscape to establish antimicrobial immunity in neonatal chicks. The metabolites highlighted in the present study can help future targeted studies to better understand immunometabolic interactions and pinpoint the key molecules or pathways contributing to immunity.

The energy sensor AMPK orchestrates metabolic and translational adaptation in expanding T helper cells.

The importance of cellular metabolic adaptation in inducing robust T cell responses is well established. However, the mechanism by which T cells link information regarding nutrient supply to clonal expansion and effector function is still enigmatic. Herein, we report that the metabolic sensor adenosine monophosphate‐activated protein kinase (AMPK) is a critical link between cellular energy demand and translational activity and, thus, orchestrates optimal expansion of T cells in vivo. AMPK deficiency did not affect T cell fate decision, activation, or T effector cell generation; however, the magnitude of T cell responses in murine in vivo models of T cell activation was markedly reduced. This impairment was global, as all T helper cell subsets were similarly sensitive to loss of AMPK which resulted in reduced T cell accumulation in peripheral organs and reduced disease severity in pathophysiologically as diverse models as T cell transfer colitis and allergic airway inflammation. T cell receptor repertoire analysis confirmed similar clonotype frequencies in different lymphoid organs, thereby supporting the concept of a quantitative impairment in clonal expansion rather than a skewed qualitative immune response. In line with these findings, in‐depth metabolic analysis revealed a decrease in T cell oxidative metabolism, and gene set enrichment analysis indicated a major reduction in ribosomal biogenesis and mRNA translation in AMPK‐deficient T cells. We, thus, provide evidence that through its interference with these delicate processes, AMPK orchestrates the quantitative, but not the qualitative, manifestation of primary T cell responses in vivo.

Metabolomics and Lipidomics: Expanding the Molecular Landscape of Exercise Biology.

Dynamic changes in circulating and tissue metabolites and lipids occur in response to exercise-induced cellular and whole-body energy demands to maintain metabolic homeostasis. The metabolome and lipidome in a given biological system provides a molecular snapshot of these rapid and complex metabolic perturbations. The application of metabolomics and lipidomics to map the metabolic responses to an acute bout of aerobic/endurance or resistance exercise has dramatically expanded over the past decade thanks to major analytical advancements, with most exercise-related studies to date focused on analyzing human biofluids and tissues. Experimental and analytical considerations, as well as complementary studies using animal model systems, are warranted to help overcome challenges associated with large human interindividual variability and decipher the breadth of molecular mechanisms underlying the metabolic health-promoting effects of exercise. In this review, we provide a guide for exercise researchers regarding analytical techniques and experimental workflows commonly used in metabolomics and lipidomics. Furthermore, we discuss advancements in human and mammalian exercise research utilizing metabolomic and lipidomic approaches in the last decade, as well as highlight key technical considerations and remaining knowledge gaps to continue expanding the molecular landscape of exercise biology.

Mitochondria and early-life adversity

Early-life adversity (ELA), which includes maltreatment, neglect, or severe trauma in childhood, increases the life-long risk for negative health outcomes. Mitochondria play a key role in the stress response and may be an important mechanism by which stress is transduced into biological risk for disease. By responding to cues from stress-signaling pathways, mitochondria interact dynamically with physiological stress responses coordinated by the central nervous, endocrine, and immune systems. Preclinical evidence suggests that alterations in mitochondrial function and structure are linked to both early stress and systemic biological dysfunction. Early clinical studies support that increased mitochondrial DNA content and altered cellular energy demands may be present in individuals with a history of ELA. Further research should investigate mitochondria as a potential therapeutic target following ELA.

Mitochondrial Function and Dysfunction in Dilated Cardiomyopathy.

Cardiac tissue requires a persistent production of energy in order to exert its pumping function. Therefore, the maintenance of this function relies on mitochondria that represent the “powerhouse” of all cardiac activities. Mitochondria being one of the key players for the proper functioning of the mammalian heart suggests continual regulation and organization. Mitochondria adapt to cellular energy demands via fusion-fission events and, as a proof-reading ability, undergo mitophagy in cases of abnormalities. Ca2+ fluxes play a pivotal role in regulating all mitochondrial functions, including ATP production, metabolism, oxidative stress balance and apoptosis. Communication between mitochondria and others organelles, especially the sarcoplasmic reticulum is required for optimal function. Consequently, abnormal mitochondrial activity results in decreased energy production leading to pathological conditions. In this review, we will describe how mitochondrial function or dysfunction impacts cardiac activities and the development of dilated cardiomyopathy.

In silico study to quantify the effect of exercise on surface GLUT4 translocation in diabetes management

Type 2 diabetes mellitus is a serious metabolic disorder affecting global health and results in number of serious life-threatening complications leading to increased mortality rate. Complications can be prevented with early diagnosis and appropriate care. International Diabetes Federation and World Health Organization suggested an urgent need of national level actions to prevent type 2 diabetes. The adverse effects of adherence to drugs as antidiabetic agents at later stages cannot be avoided. Hence, alternative therapies are constantly explored by the researchers to mitigate type 2 diabetes. Exercise has a significant impact on the improvement of type 2 diabetes. Metabolic adaptations are provoked by exercise in skeletal muscle cells. AMP-activated protein kinase (AMPK) is an important molecule in managing these adaptations. In response to cellular energy demand, the activity of AMPK increases, which then triggers the glucose transporter 4 (GLUT4) translocation through signaling pathways proposed in the present model. The quantification of exercise on insulin resistance reduction is not well established. The modeling of the effects of physical exercise on signaling pathways in the disease condition is still a challenging task. In silico studies are useful to investigate effect of exercise in diabetes. This research work presents a model to quantify the effect of exercise on the GLUT4 translocation. The result provides effect of exercise in the improvement of insulin resistance developed by type 2 diabetes. The study is useful for establishing in vivo model correlating actual effect of exercise in diabetes management.

The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation

Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element-binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.