Alterations In Mitochondrial Energy Metabolism Research Articles

Measuring Brain Temperature in Youth Bipolar Disorder Using a Novel Magnetic Resonance Imaging Approach: A Proof-of-concept Study.

There is evidence of alterations in mitochondrial energy metabolism and cerebral blood flow (CBF) in adults and youth with bipolar disorder (BD). Brain thermoregulation is based on the balance of heat-producing metabolism and heat-dissipating mechanisms, including CBF. To examine brain temperature, and its relation to CBF, in relation to BD and mood symptom severity in youth. This study included 25 youth participants (age 17.4 ± 1.7 years; 13 BD, 12 control group (CG)). Magnetic resonance spectroscopy data were acquired to obtain brain temperature in the left anterior cingulate cortex (ACC) and the left precuneus. Regional estimates of CBF were provided by arterial spin labeling imaging. Analyses used general linear regression models, covarying for age, sex, and psychiatric medications. Brain temperature was significantly higher in BD compared to CG in the precuneus. A higher ratio of brain temperature to CBF was significantly associated with greater depression symptom severity in both the ACC and precuneus within BD. Analyses examining the relationship of brain temperature or CBF with depression severity score did not reveal any significant finding in the ACC or the precuneus. The current study provides preliminary evidence of increased brain temperature in youth with BD, in whom reduced thermoregulatory capacity is putatively associated with depression symptom severity. Evaluation of brain temperature and CBF in conjunction may provide valuable insight beyond what can be gleaned by either metric alone. Larger prospective studies are warranted to further evaluate brain temperature and its association with CBF concerning BD.

Plasma methylmalonic acid predicts risk of acute myocardial infarction and mortality in patients with coronary heart disease: A prospective 2-cohort study.

Elevated plasma methylmalonic acid (MMA) is reported in patients with established coronary heart disease (CHD) and is considered a marker of vitamin B12 deficiency. Moreover, MMA-dependent reactions have been linked to alterations in mitochondrial energy metabolism and oxidative stress, key features in the pathophysiology of cardiovascular diseases (CVDs). We examined whether plasma MMA prospectively predicted the long-term risk of acute myocardial infarction (AMI) and mortality. Using Cox modeling, we estimated hazard ratios (HRs) for endpoints according to per 1-SD increment of log-transformed plasma MMA in two independent populations: the Western Norway Coronary Angiography Cohort (WECAC) (patients evaluated for CHD; n=4137) and the Norwegian Vitamin Trial (NORVIT) (patients hospitalized with AMI; n=3525). In WECAC and NORVIT, 12.8% and 18.0% experienced an AMI, whereas 21.8% and 19.9% died, of whom 45.5% and 60.3% from CVD-related causes during follow-up (range 3-11 years), respectively. In WECAC, age- and gender-adjusted HRs (95% confidence interval) were 1.18 (1.09-1.28), 1.25 (1.18-1.33), and 1.28 (1.17-1.40) for future AMI, total mortality, and CVD mortality, respectively. Corresponding risk estimates were 1.19 (1.10-1.28), 1.22 (1.14-1.31), and 1.30 (1.19-1.42) in NORVIT. These estimates were only slightly attenuated after multivariable adjustments. Across both cohorts, the MMA-risk association was stronger in older adults, women, and non-smokers. Elevated MMA was associated with an increased risk of AMI and mortality in patients with suspected or verified CHD.

Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy: an in silico study.

Diabetic cardiomyopathy is a leading cause of heart failure in diabetes. At the cellular level, diabetic cardiomyopathy leads to altered mitochondrial energy metabolism and cardiomyocyte ultrastructure. We combined electron microscopy (EM) and computational modelling to understand the impact of diabetes-induced ultrastructural changes on cardiac bioenergetics. We collected transverse micrographs of multiple control and type I diabetic rat cardiomyocytes using EM. Micrographs were converted to finite-element meshes, and bioenergetics was simulated over them using a biophysical model. The simulations also incorporated depressed mitochondrial capacity for oxidative phosphorylation (OXPHOS) and creatine kinase (CK) reactions to simulate diabetes-induced mitochondrial dysfunction. Analysis of micrographs revealed a 14% decline in mitochondrial area fraction in diabetic cardiomyocytes, and an irregular arrangement of mitochondria and myofibrils. Simulations predicted that this irregular arrangement, coupled with the depressed activity of mitochondrial CK enzymes, leads to large spatial variation in adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio profile of diabetic cardiomyocytes. However, when spatially averaged, myofibrillar ADP/ATP ratios of a cardiomyocyte do not change with diabetes. Instead, average concentration of inorganic phosphate rises by 40% owing to lower mitochondrial area fraction and dysfunction in OXPHOS. These simulations indicate that a disorganized cellular ultrastructure negatively impacts metabolite transport in diabetic cardiomyopathy.This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

Reduced mitochondrial fission and impaired energy metabolism in human primary skeletal muscle cells of Megaconial Congenital Muscular Dystrophy

Megaconial Congenital Muscular Dystrophy (CMD) is a rare autosomal recessive disorder characterized by enlarged mitochondria located mainly at the periphery of muscle fibers and caused by mutations in the Choline Kinase Beta (CHKB) gene. Although the pathogenesis of this disease is not well understood, there is accumulating evidence for the presence of mitochondrial dysfunction. In this study, we aimed to investigate whether imbalanced mitochondrial dynamics affects mitochondrial function and bioenergetic efficiency in skeletal muscle cells of Megaconial CMD. Immunofluorescence, confocal and transmission electron microscopy studies revealed impaired mitochondrial network, morphology, and localization in primary skeletal muscle cells of Megaconial CMD. The organelle disruption was specific only to skeletal muscle cells grown in culture. The expression levels of mitochondrial fission proteins (DRP1, MFF, FIS1) were found to be decreased significantly in both primary skeletal muscle cells and tissue sections of Megaconial CMD by Western blotting and/or immunofluorescence analysis. The metabolomic and fluxomic analysis, which were performed in Megaconial CMD for the first time, revealed decreased levels of phosphonucleotides, Krebs cycle intermediates, ATP, and altered energy metabolism pathways. Our results indicate that reduced mitochondrial fission and altered mitochondrial energy metabolism contribute to mitochondrial dysmorphology and dysfunction in the pathogenesis of Megaconial CMD.

Mitochondrial damage in renal epithelial cells is potentiated by protein exposure in propionic aciduria.

Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Due to inefficient propionate catabolism patients are endangered by life-threatening ketoacidotic crisis. Protein and amino acid restriction are major therapeutic pillars. However, long-term complications like neurological deterioration and cardiac abnormalities cannot be prevented. Chronic kidney disease (CKD), which is a well-known characteristic of methylmalonic aciduria two enzymatic steps downstream from PCC, has been recognized as a novel late-onset complication in PA. The pathophysiology of CKD in PA is unclear. We investigated mitochondrial structure and metabolism in human renal tubular cells of healthy controls and PA patients. The cells were exposed to either standard cell culture conditions (NT), high protein (HP) or high concentrations of isoleucine and valine (I/V). Mitochondrial morphology changed to condensed, fractured morphology in PA cells irrespective of the cell culture medium. HP and I/V exposure, however, potentiated oxidative stress in PA cells. Mitochondrial mass was enriched in PA cells, and further increased by HP and I/V exposure suggesting a need for compensation. Alterations in the tricarboxylic acid cycle intermediates and accumulation of medium- and long-chain acylcarnitines pointed to altered mitochondrial energy metabolism. Mitophagy was silenced while autophagy as cellular defense mechanisms was highly active in PA cells. The data demonstrate that PA is associated with renal mitochondrial damage which is aggravated by protein and I/V load. Preservation of mitochondrial energy homeostasis in renal cells may be a potential future therapeutic target.

Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction

Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother–infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers. Good caregiving by normal mothers did not reverse prenatal trauma-induced behaviors, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting. The behavioral deficits were associated with profound changes in the brain metabotranscriptome. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults exposed prenatally to trauma indicated mitochondrial dysfunction and epigenetic mechanisms. Bioinformatic analyses revealed stress- and hypoxia-response metabolic pathways in the neonates, which produced long-lasting alterations in mitochondrial energy metabolism and epigenetic processes (DNA and chromatin modifications). Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.

Cerebellar and multi-system metabolic reprogramming associated with trauma exposure and post-traumatic stress disorder (PTSD)-like behavior in mice

Mitochondrial metabolism is increasingly implicated in psychopathologies and mood disorders, including post-traumatic stress disorder (PTSD). We recently reported that mice exposed to a novel paradigm for the induction of PTSD-like behavior displayed reduced mitochondrial electron transport chain (mtETC) complex activity as well as decreased multi-system fatty acid oxidation (FAO) flux. Based on these results, we hypothesized that stressed and PTSD-like animals would display evidence of metabolic reprogramming in both cerebellum and plasma consistent with increased energetic demand, mitochondrial metabolic reprogramming, and increased oxidative stress.We performed targeted metabolomics in both cerebellar tissue and plasma, as well as untargeted nuclear magnetic resonance (NMR) spectroscopy in the cerebellum of 6 PTSD-like and 7 resilient male mice as well as 7 trauma-naïve controls. We identified numerous differences in amino acids and tricarboxylic acid (TCA) cycle metabolite concentrations in the cerebellum and plasma consistent with altered mitochondrial energy metabolism in trauma exposed and PTSD-like animals. Pathway analysis identified metabolic pathways with significant metabolic pathway shifts associated with trauma exposure, including the tricarboxylic acid cycle, pyruvate, and branched-chain amino acid metabolism in both cerebellar tissue and plasma. Altered glutamine and glutamate metabolism, and arginine biosynthesis was evident uniquely in cerebellar tissue, while ketone body levels were modified in plasma. Importantly, we also identified several cerebellar metabolites (e.g. choline, adenosine diphosphate, beta-alanine, taurine, and myo-inositol) that were sufficient to discriminate PTSD-like from resilient animals.This multilevel analysis provides a comprehensive understanding of local and systemic metabolite fingerprints associated with PTSD-like behavior, and subsequently altered brain bioenergetics. Notably, several transformed metabolic pathways observed in the cerebellum were also reflected in plasma, connecting central and peripheral biosignatures of PTSD-like behavior. These preliminary findings could direct further mechanistic studies and offer insights into potential metabolic interventions, either pharmacological or dietary, to improve PTSD resilience.

Mitochondrial Dynamics and Bioenergetic Alteration During Inflammatory Activation of Astrocytes.

Mitochondria are essential cellular organelles that act as metabolic centers and signaling platforms and have been identified as an important subcellular target in a broad range of neuropathologies. Studies on the role of mitochondria in neurological disorders have primarily focused on neurons. However, dysfunctional mitochondria in glial cells, particularly astrocytes, have recently gained research attention due to their close involvement in neuroinflammation and metabolic and neurodegenerative disorders. Furthermore, alterations in mitochondrial energy metabolism in astrocytes have been reported to modulate cellular morphology and activity and induce the release of diverse proinflammatory mediators. Moreover, emerging evidence suggests that dysregulation of mitochondrial dynamics characterized by aberrant fission and fusion events in glial cells is closely associated with the inflammatory activation of glia. In this mini-review, we cover the recent advances in the molecular aspects of astrocytic mitochondrial dynamics and their metabolic changes under the pathological conditions of the central nervous system (CNS).

Progressive Alterations of Mitochondrial Function in the Kidney and Heart During the Development of Salt‐Induced Hypertension

IntroductionHypertension is a multi‐factorial disease and a leading cause of morbidity and mortality globally. Nearly half of these individuals are sensitive to dietary salt intake with the kidney and oxidative stress playing a key role in this disease leading to eventual failure of both the kidney and heart. Although oxidative stress and mitochondrial dysfunction in the kidney and heart have been studied in various models of hypertension, progressive alterations of mitochondrial function and development of oxidative stress in these two organs have not been studies in parallel during the development of hypertension. The goal of the present study was to investigate progressive alterations in mitochondrial energy metabolism in both the kidney and heart concurrently in the Dahl salt‐sensitive (SS) rats during the development of hypertension when rats were switched from a 0.4% NaCl (LS) to a 4% NaCl (HS) diet.MethodMitochondria were isolated from the ventricles of the heart and outer medulla (OM) and cortex of the kidney of SS rats fed a LS diet since weaning and studied at days 3, 7, 14 & 21 of a HS diet feeding. Oxygen consumption rates (OCR) were measured in mitochondria energized with pyruvate + malate as substrates for 3 different respiratory states using an Oroboros Oxygraph‐2k respirometer. This includes a) leak state (energized mitochondria in the absence of ADP), b) ADP‐stimulated state, and c) uncoupled state (energized mitochondria in the presence of an uncoupler FCCP).ResultsA biphasic pattern of ADP‐stimulated OCR with progressive uncoupling was observed in both the kidney (OM & cortex) and heart mitochondria. In kidney, mitochondrial efficiency for ATP synthesis was increased in the early phase of hypertension (3 & 7 days) but was severely compromised in the established phase of hypertension (14 & 21 days). Cardiac mitochondria also showed a similar pattern, however the reduced mitochondrial efficiency for ATP synthesis occurred at a later time, specifically at day 21. This decreased mitochondrial efficiency was hypothesized to be associated with higher levels of uncoupling, ROS production, and oxidative stress in both organs due to mitochondrial ROS‐cellular ROS crosstalk. To test this, experiments were performed in SS rats with double knock out (DKO) of the Nox family of NADPH oxidases: Nox4 and p67phox cytosolic subunit of Nox2 (SSp67phox−/−/Nox4−/−) and determined the role of mitochondrial ROS in stimulating cellular ROS production, particularly by membrane Noxs, and vice versa. Specifically, the DKO SS rats were fed a HS diet and isolated mitochondrial OCR was studied at days 7 and 14. DKO SS rats fed a HS diet showed no significant differences in mitochondrial OCR as compared to the control group (LS diet) in the kidney (OM & cortex) and heart.ConclusionOur data suggest that a HS diet in SS rats results initially in increased efficiency of renal cortical and medullary mitochondrial energy production during the 1st week of a HS diet followed by an enhanced ROS production with mitochondrial uncoupling and reduced efficiency of ATP production by the 3rd week. Similar changes occurred in the heart but 1–2 weeks following the changes observed in the kidney.Support or Funding InformationP01‐GM066730, P01‐HL116264

Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome.

Impaired energy metabolism may play a role in the pathogenesis of neurodevelopmental disorders including fragile X syndrome (FXS). We checked brain energy status and some aspects of cell bioenergetics, namely the activity of key glycolytic enzymes, glycerol-3-phosphate shuttle and mitochondrial respiratory chain (MRC) complexes, in the cerebral cortex of the Fmr1 knockout (KO) mouse model of FXS. We found that, despite a hyperactivation of MRC complexes, adenosine triphosphate (ATP) production via mitochondrial oxidative phosphorylation (OXPHOS) is compromised, resulting in brain energy impairment in juvenile and late-adult Fmr1 KO mice. Thus, an altered mitochondrial energy metabolism may contribute to neurological impairment in FXS.

Mechanisms of Energy Metabolism in Skeletal Muscle Mitochondria Following Radiation Exposure.

An understanding of cellular processes that determine the response to ionizing radiation exposure is essential for improving radiotherapy and assessing risks to human health after accidental radiation exposure. Radiation exposure leads to many biological effects, but the mechanisms underlying the metabolic effects of radiation are not well known. Here, we investigated the effects of radiation exposure on the metabolic rate and mitochondrial bioenergetics in skeletal muscle. We show that ionizing radiation increased mitochondrial protein and mass and enhanced proton leak and mitochondrial maximal respiratory capacity, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, mice and cells treated with radiation became energetically efficient and displayed increased fatty acid and amino acid oxidation metabolism through the citric acid cycle. Finally, we demonstrate that radiation-induced alterations in mitochondrial energy metabolism involved adenosine monophosphate-activated kinase signaling in skeletal muscle. Together, these results demonstrate that alterations in mitochondrial mass and function are important adaptive responses of skeletal muscle to radiation.

Streptozotocin-induced molecular and metabolic targets in pancreatic beta-cell toxicity

Background/Aim: The prevalence of diabetes is on the rise globally causing excessive burden on the health systems. Pancreatic beta-cell mass destruction/neogenesis/proliferation (seen in type1diabetes) and/or malfunction (type 2 diabetes) have been implicated in the aetiology, pathology, progression as well as in responses towards therapies and disease managements. Oxidative stress and alterations in mitochondrial energy metabolism play important roles in diabetes-induced cellular complications. Several studies, including our own, have suggested that Rin-5F pancreatic beta cells are extremely susceptible to oxidative stress due to excessive production of endogenous and exogenous reactive oxygen/nitrogen species (ROS/RNS) and low antioxidant defences, particularly, associated with GSH metabolism. Our aim was to investigate the molecular mechanism of streptozotocin (STZ), a beta cell-specific antibiotic, cytotoxicity in pancreatic cells. Methods: Rin-5F cells were treated with STZ under varying conditions to study oxidative stress-related changes. Results: Our studies have suggested that treatment of Rin-5F cells with STZ, inhibits cell survival and induces cytotoxicity by altering cellular survival and apoptotic signalling and gene expressions. Increased oxidative stress with increased DNA fragmentation and oxidative protein carbonylation were seen in STZ-treated cells. We also observed that beta cells treated with high glucose (up to 25mM) exhibited enhanced cytotoxicity. Cells exposed to conditions mimicking diabetes (hyperglycaemia) were under elevated oxidative stress and showed increased apoptosis and altered redox homeostasis leading to increased cytotoxicity. N-acetyl cysteine (NAC) treatment attenuated these changes in STZ-treated cells. Conclusion: These results may have implications in understanding the mechanism of beta cell survival/death in response to potential therapeutics/managements as well as in the aetiology and pathophysiology of diabetes.

Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Background/Aims: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic β-cells. Methods: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH-dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques. Results: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells. Conclusion: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic β-cells against STZ-induced cytotoxicity.

Advanced glycation end products‑induced mitochondrial energy metabolism dysfunction alters proliferation of human umbilical vein endothelial cells.

Advanced glycation end products (AGEs) restrain the proliferation of endothelial cells, which is an important determinant of diabetic vasculopathy. Mitochondrial biogenesis serves an essential role in cellular adaptation and repair. The current study aimed to investigate alterations in mitochondrial energy metabolism in human umbilical vein endothelial cells (HUVECs) and the latent mechanism regulated by AGEs. The proliferation of cultured HUVECs stimulated with AGEs was detected using an MTT assay and a real‑time cell analyzer (RTCA). Mitochondrial energy metabolism was measured using a Seahorse metabolic flux analyzer. Mitochondrial membrane potential was detected under fluorescence microscopy following staining with tetraethylrhodamine and MitoTracker Red. Respiratory chain complexes I‑V were detected using western blotting. MTT and RTCA assays demonstrated that AGEs treatment significantly inhibited the viability and proliferation of HUVECs when compared with bovine serum albumin treatment. Results from the Seahorse metabolic flux analyzer indicated that mitochondrial aerobic respiration and glycolysis declined following AGEs treatment. In addition, mitochondrial membrane potential and the expression of mitochondrial respiration chain complexesI/II/III/IV/V notably decreased in the presence of AGEs. In conclusion, the results of the present study indicated that AGEs exhibited an inhibitory effect on the proliferation in HUVECs potentially by mediating the dysfunction of mitochondrial energy metabolism and glycolysis. This may provide a new consideration for therapeutic methods in diabetic vascular complications.

Determination of muscle mitochondrial respiratory capacity in Standardbred racehorses as an aid to predicting exertional rhabdomyolysis

This prospective cohort study evaluated the potential of high-resolution respirometry applied to permeabilized muscle fibers for fitness evaluation in French Standardbred racehorses.Fitness evaluation by means of respirometric parameters did not correlate with racing performance registered over the following racing season. However, altered mitochondrial energy metabolism was associated with higher risk of developing exertional rhabdomyolysis, a common cause of exercise intolerance in racehorses. These data represent a first step towards establishing reference values for muscle OXPHOS capacity in this breed.

Tipping the metabolic scales towards increased longevity in mammals.

A hallmark of ageing is dysfunction in nutrient signalling pathways that regulate glucose homeostasis, negatively affecting whole-body energy metabolism and ultimately increasing the organism's susceptibility to disease. Maintenance of insulin sensitivity depends on functional mitochondrial networks, but is compromised by alterations in mitochondrial energy metabolism during ageing. Here we discuss metabolic paradigms that influence mammalian longevity, and highlight recent advances in identifying fundamental signalling pathways that influence metabolic health and ageing through mitochondrial perturbations.

Seed-specific expression of a feedback-insensitive form of CYSTATHIONINE-γ-SYNTHASE in Arabidopsis stimulates metabolic and transcriptomic responses associated with desiccation stress.

With an aim to elucidate novel metabolic and transcriptional interactions associated with methionine (Met) metabolism in seeds, we have produced transgenic Arabidopsis (Arabidopsis thaliana) seeds expressing a feedback-insensitive form of CYSTATHIONINE-γ-SYNTHASE, a key enzyme of Met synthesis. Metabolic profiling of these seeds revealed that, in addition to higher levels of Met, the levels of many other amino acids were elevated. The most pronounced changes were the higher levels of stress-related amino acids (isoleucine, leucine, valine, and proline), sugars, intermediates of the tricarboxylic acid cycle, and polyamines and lower levels of polyols, cysteine, and glutathione. These changes reflect stress responses and an altered mitochondrial energy metabolism. The transgenic seeds also had higher contents of total proteins and starch but lower water contents. In accordance with the metabolic profiles, microarray analysis identified a strong induction of genes involved in defense mechanisms against osmotic and drought conditions, including those mediated by the signaling cascades of ethylene and abscisic acid. These changes imply that stronger desiccation processes occur during seed development. The expression levels of transcripts controlling the levels of Met, sugars, and tricarboxylic acid cycle metabolites were also significantly elevated. Germination assays showed that the transgenic seeds had higher germination rates under salt and osmotic stresses and in the presence of ethylene substrate and abscisic acid. However, under oxidative conditions, the transgenic seeds displayed much lower germination rates. Altogether, the data provide new insights on the factors regulating Met metabolism in Arabidopsis seeds and on the mechanisms by which elevated Met levels affect seed composition and behavior.

Mitochondrial Defects And Their Role In Development Of Prostate Cancer

Introduction and Objectives: One of the characteristic changes of tumor formation is accumulation of genetic disorders in mitochondrial and nuclear genome. Mitochondrial disorders, from its side, are responsible for failure of metabolism, apoptosis, cell growth, formation of reactive oxygen species, etc. Overprpoduction of reactive oxygen species (ROS) significantly impacts the respiration chain enzymes and entirely the antioxidant system of mitochondria. Finally this may become a favorable condition for normal cells transformation.The purpose of the presented work was to study the mitochondrial defects and to establish their role in prostate cancer development.Results: Experimental results demonstrate significant increase of the activity of mitochondrial succinate dehydrogenaze (complex II) of the malignant epithelial cells of prostate, and slight changes in cytochrome oxydase (complex IV) activity. Also significant activation of the antioxidant system (glutathione-dependant system) of mitochondria in prostate malignant epithelial cells was revealed.Conclusion: The above mentioned mitochondrial changes (II and IV complexes of respiration chain, activity of the antioxidant system) partially demonstrate the alterations in mitochondrial energy metabolism, which from its side, may indicate to resistance of prostate cancer cells and correspondingly to intensification of proliferation processes.

Chronic hypoxia-induced alterations in mitochondrial energy metabolism are not reversible in rat heart ventricles

Chronic hypoxia alters mitochondrial energy metabolism. In the heart, oxidative capacity of both ventricles is decreased after 3 weeks of chronic hypoxia. The aim of this study was to evaluate the reversal of these metabolic changes upon normoxia recovery. Rats were exposed to a hypobaric environment for 3 weeks and then subjected to a normoxic environment for 3 weeks (normoxia-recovery group) and compared with rats maintained in a normoxic environment (control group). Mitochondrial energy metabolism was differentially examined in both left and right ventricles. Oxidative capacity (oxygen consumption and ATP synthesis) was measured in saponin-skinned fibers. Activities of mitochondrial respiratory chain complexes and antioxidant enzymes were measured on ventricle homogenates. Morphometric analysis of mitochondria was performed on electron micrographs. In normoxia-recovery rats, oxidative capacities of right ventricles were decreased in the presence of glutamate or palmitoyl carnitine as substrates. In contrast, oxidation of palmitoyl carnitine was maintained in the left ventricle. Enzyme activities of complexes III and IV were significantly decreased in both ventricles. These functional alterations were associated with a decrease in numerical density and an increase in size of mitochondria. Finally, in the normoxia-recovery group, the antioxidant enzyme activities (catalase and glutathione peroxidase) increased. In conclusion, alterations of mitochondrial energy metabolism induced by chronic hypoxia are not totally reversible. Reactive oxygen species could be involved and should be investigated under such conditions, since they may represent a therapeutic target.

Abnormal Cingulate and Prefrontal Cortical Neurochemistry in Major Depression After Electroconvulsive Therapy

Metabolic changes after electroconvulsive therapy (ECT) have been described in depressed patients, but results are heterogeneous. To determine the concentrations of N-acetyl-aspartate (NAA), choline-containing compounds, creatine + phosphocreatine (tCr), and glutamate in the left dorsolateral prefrontal cortex (DLPFC) and left anterior cingulum of depressed patients before and after ECT, we used proton magnetic resonance spectroscopy. Metabolite concentrations in the DLPFC and anterior cingulum were determined in 25 patients with major depressive disorder (MDD) and 27 healthy control subjects using the point resolved spectroscopy sequence. Neuropsychological and clinical parameters were determined before and after nine sessions of right unilateral ultrabrief pulse ECT. In the cingulum, baseline glutamate and NAA levels were decreased in depressed patients. High glutamate at baseline predicted a greater treatment response. After ECT, increased NAA levels were observed in responders to treatment and tCr levels were significantly decreased across all depressive patients. In the left DLPFC, NAA levels were significantly decreased in responders to ECT compared with nonresponders. Autobiographic memory was deteriorated in all patients after ECT. Low glutamatergic state in depressive patients emphasizes the role of dysfunctional glutamatergic neurotransmission in the pathophysiology of MDD. The low NAA level at baseline in the patients supports neurodegenerative changes in MDD. N-acetyl-aspartate levels might serve as early surrogate marker for dynamic metabolic changes due to ECT, reflecting both neuroprotection and lowered neuronal viability. The tCr decrease in the cingulum suggests altered mitochondrial energy metabolism.