Human HDL subclasses modulate energy metabolism in skeletal muscle cells.

In addition to its antiatherogenic role, HDL reportedly modulates energy metabolism at the whole-body level. HDL functionality is associated with its structure and composition, and functional activities can differ between HDL subclasses. Therefore, we studied if HDL2 and HDL3, the two major HDL subclasses, are able to modulate energy metabolism of skeletal muscle cells. Differentiated mouse and primary human skeletal muscle myotubes were used to investigate the influences of human HDL2 and HDL3 on glucose and fatty uptake and oxidation. HDL-induced changes in lipid distribution and mRNA expression of genes related to energy substrate metabolism, mitochondrial function, and HDL receptors were studied with human myotubes. Additionally, we examined the effects of apoA-I and discoidal, reconstituted HDL particles on substrate metabolism. In mouse myotubes, HDL subclasses strongly enhanced glycolysis upon high and low glucose concentrations. HDL3 caused a minor increase in ATP-linked respiration upon glucose conditioning but HDL2 improved complex I-mediated mitochondrial respiration upon fatty acid treatment. In human myotubes, glucose metabolism was attenuated but fatty acid uptake and oxidation were markedly increased by both HDL subclasses, which also increased mRNA expression of genes related to fatty acid metabolism and HDL receptors. Finally, both HDL subclasses induced incorporation of oleic acid into different lipid classes. These results, demonstrating that HDL subclasses enhance fatty acid oxidation in human myotubes but improve anaerobic metabolism in mouse myotubes, support the role of HDL as a circulating modulator of energy metabolism. Exact mechanisms and components of HDL causing the change, require further investigation.

Mitochondrial function and sexual selection: can physiology resolve the 'lek paradox'?

Across many taxa, males use elaborate ornaments or complex displays to attract potential mates. Such sexually selected traits are thought to signal important aspects of male 'quality'. Female mating preferences based on sexual traits are thought to have evolved because choosy females gain direct benefits that enhance their lifetime reproductive success (e.g. greater access to food) and/or indirect benefits because high-quality males contribute genes that increase offspring fitness. However, it is difficult to explain the persistence of female preferences when males only provide genetic benefits, because female preferences should erode the heritable genetic variation in fitness that sexually selected traits signal. This 'paradox of the lek' has puzzled evolutionary biologists for decades, and inspired many hypotheses to explain how heritable variation in sexually selected traits is maintained. Here, we discuss how factors that affect mitochondrial function can maintain variation in sexually selected traits despite strong female preferences. We discuss how mitochondrial function can influence the expression of sexually selected traits, and we describe empirical studies that link the expression of sexually selected traits to mitochondrial function. We explain how mothers can affect mitochondrial function in their offspring by (a) influencing their developmental environment through maternal effects and (b) choosing a mate to increase the compatibility of mitochondrial and nuclear genes (i.e. the 'mitonuclear compatibility model of sexual selection'). Finally, we discuss how incorporating mitochondrial function into models of sexual selection might help to resolve the paradox of the lek, and we suggest avenues for future research.

The role of cyanoalanine synthase and alternative oxidase in promoting salt stress tolerance in Arabidopsis thaliana.

BACKGROUND: Cyanide is a toxic chemical that inhibits cellular respiration. In plants, cyanide can be produced by themselves, especially under stressful conditions. Cyanoalanine synthase (CAS) is a key enzyme involved in plant cyanide detoxification. There are three genes encoding CAS in Arabidopsis thaliana, but the roles of these genes in the plant's response to stress are less studied. In addition, it is known that alternative oxidase (AOX) mediates cyanide-resistant respiration, but the relationship between CAS and AOX in regulating the plant stress response remains largely unknown. RESULTS: Here, the effects of the overexpression or mutation of these three CAS genes on salt stress tolerance were investigated. The results showed that under normal conditions, the overexpression or mutation of the CAS genes had no significant effect on the seed germination and growth of Arabidopsis thaliana compared with wild type (WT). However, under 50, 100, and 200 mM NaCl conditions, the seeds overexpressing CAS genes showed stronger salt stress resistance, i.e., higher germination speed than WT seeds, especially those that overexpressed the CYS-C1 and CYS-D1 genes. In contrast, the seeds with CAS gene mutations exhibited salt sensitivity, and their germination ability and growth were significantly damaged by 100 and 200 mM NaCl. Importantly, this difference in salt stress resistance became more pronounced in CAS-OE, WT, and mutant seeds with increasing salt concentration. The CAS-OE seeds maintained higher respiration rates than the WT and CAS mutant seeds under salt stress conditions. The cyanide contents in CAS mutant seeds were approximately 3 times higher than those in WT seeds and more than 5 times higher than those in CAS-OE seeds. In comparison, plants overexpressing CYS-C1 had the fastest detoxification of cyanide and the best salt tolerance, followed by those overexpressing CYS-D1 and CYS-D2. Furthermore, less hydrogen sulfide (H2S) was observed in CAS-OE seedlings than in WT seedlings under long-term salt stress conditions. Nonetheless, the lack of AOX impaired CAS-OE-mediated plant salt stress resistance, suggesting that CAS and AOX interact to improve salt tolerance is essential. The results also showed that CAS and AOX contributed to the reduction in oxidative damage by helping maintain relatively high levels of antioxidant enzyme activity. CONCLUSION: In summary, the findings of the present study suggest that overexpression of Arabidopsis CAS family genes plays a positive role in salt stress tolerance and highlights the contribution of AOX to CAS-mediated plant salt resistance, mainly by reducing cyanide and H2S toxicity.

Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy.

Nitric oxide can interact with a wide range of proteins including many that are involved in metabolism. In this review we have summarized the effects of NO on glycolysis, fatty acid metabolism, the TCA cycle, and oxidative phosphorylation with reference to skeletal muscle. Low to moderate NO concentrations upregulate glucose and fatty acid oxidation, while higher NO concentrations shift cellular reliance toward a fully glycolytic phenotype. Moderate NO production directly inhibits pyruvate dehydrogenase activity, reducing glucose-derived carbon entry into the TCA cycle and subsequently increasing anaploretic reactions. NO directly inhibits aconitase activity, increasing reliance on glutamine for continued energy production. At higher or prolonged NO exposure, citrate accumulation can inhibit multiple ATP-producing pathways. Reduced TCA flux slows NADH/FADH entry into the ETC. NO can also inhibit the ETC directly, further limiting oxidative phosphorylation. Moderate NO production improves mitochondrial efficiency while improving O2 utilization increasing whole-body energy production. Long-term bioenergetic capacity may be increased because of NO-derived ROS, which participate in adaptive cellular redox signaling through AMPK, PCG1-α, HIF-1, and NF-κB. However, prolonged exposure or high concentrations of NO can result in membrane depolarization and opening of the MPT. In this way NO may serve as a biochemical rheostat matching energy supply with demand for optimal respiratory function.

Mitochondrial matrix-localized Src kinase regulates mitochondrial morphology.

The architecture of mitochondria adapts to physiological contexts: while mitochondrial fragmentation is usually associated to quality control and cell death, mitochondrial elongation often enhances cell survival during stress. Understanding how these events are regulated is important to elucidate how mitochondrial dynamics control cell fate. Here, we show that the tyrosine kinase Src regulates mitochondrial morphology. Deletion of Src increased mitochondrial size and reduced cellular respiration independently of mitochondrial mass, mitochondrial membrane potential or ATP levels. Re-expression of Src targeted to the mitochondrial matrix, but not of Src targeted to the plasma membrane, rescued mitochondrial morphology in a kinase activity-dependent manner. These findings highlight a novel function for Src in the control of mitochondrial dynamics.

Effect of Sirolimus/Metformin Co-Treatment on Hyperglycemia and Cellular Respiration in BALB/c Mice.

Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4-6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.

Tissue-Oxygen-Adaptation of Bone Marrow-Derived Mesenchymal Stromal Cells Enhances Their Immunomodulatory and Pro-Angiogenic Capacity, Resulting in Accelerated Healing of Chemical Burns.

Transplantation of mesenchymal stromal cells (MSCs) provides a powerful tool for the management of multiple tissue injuries. However, poor survival of exogenous cells at the site of injury is a major complication that impairs MSC therapeutic efficacy. It has been found that tissue-oxygen adaptation or hypoxic pre-conditioning of MSCs could improve the healing process. Here, we investigated the effect of low oxygen tension on the regenerative potential of bone-marrow MSCs. It turned out that incubation of MSCs under a 5% oxygen atmosphere resulted in increased proliferative activity and enhanced expression of multiple cytokines and growth factors. Conditioned growth medium from low-oxygen-adapted MSCs modulated the pro-inflammatory activity of LPS-activated macrophages and stimulated tube formation by endotheliocytes to a much higher extent than conditioned medium from MSCs cultured in a 21% oxygen atmosphere. Moreover, we examined the regenerative potential of tissue-oxygen-adapted and normoxic MSCs in an alkali-burn injury model on mice. It has been revealed that tissue-oxygen adaptation of MSCs accelerated wound re-epithelialization and improved the tissue histology of the healed wounds in comparison with normoxic MSC-treated and non-treated wounds. Overall, this study suggests that MSC adaptation to 'physiological hypoxia' could be a promising approach for facilitating skin injuries, including chemical burns.

Targeting ERK3/MK5 complex for treatment of obesity and diabetes.

Kinases represent one of the largest druggable families of proteins. Importantly, many kinases are aberrantly activated/de-activated in multiple organs during obesity, which contributes to the development of diabetes and associated diseases. Previous results indicate that the complex between Extracellular-regulated kinase 3 (ERK3) and Mitogen-Activated Protein Kinase (MAPK)-activated protein kinase 5 (MK5) suppresses energy dissipation and promotes fatty acids (FAs) output in adipose tissue and, therefore promotes obesity and diabetes. However, the therapeutic potential of targeting this complex at the systemic level has not been fully explored. Here we applied a translational approach to target the ERK3/MK5 complex in mice. Importantly, deletion of ERK3 in the whole body or administration of MK5-specific inhibitor protects against obesity and promotes insulin sensitivity. Finally, we show that the expression of ERK3 and MK5 correlates with the degree of obesity and that ERK3/MK5 complex regulates energy dissipation in human adipocytes. Altogether, we demonstrate that ERK3/MK5 complex can be targeted in vivo to preserve metabolic health and combat obesity and diabetes.

Detrimental effects of fructose on mitochondria in mouse motor neurons and on C. elegans healthspan.

BACKGROUND: Fructose-common sweetener, consumed in large quantities, is now known to be associated with various metabolic diseases. Recent reports suggest fructose's involvement in neurodegeneration, neurotoxicity, and neuroinflammation. But, its impact at cellular and subcellular level and on energy metabolism, especially, mitochondrial bioenergetics, in neurons is not known. OBJECTIVES: To study the adverse effects of high fructose in general, and on the mitochondria in a spinal cord motor neuron cell line, NSC-34, in vitro, and Caenorhabditis elegans in vivo. METHODS: NSC-34 was treated with 0.5%-5% of fructose for different time periods. Fructose's effect on cell viability (MTT assay), metabolic activity (XF24 Seahorse assays) and C. elegans, chronically fed with 5% fructose and alteration in healthspan/mitochondria was monitored. RESULTS: In NSC-34: Fructose at 4-5% elicits 60% cell death. Unlike 1%, 5% fructose (F5%) decreased mitochondrial membrane potential by 29%. Shockingly, 6hours F5% treatment almost abolished mitochondrial respiration - basal-respiration (∨123%), maximal-respiration (∨ 95%) and spare-respiratory-capacity (∨ 83%) and ATP production (∨98%) as revealed by XF 24- Seahorse assays. But non - mitochondrial respiration was spared. F5% treatment for 48hrs resulted in the total shutdown of respiratory machinery including glycolysis. Chronic feeding of wildtype C.elegans to F5% throughout, shortened lifespan by ~3 days (∨ 17%), progressively reduced movement (day-2 -∨10.25%, day-5 -∨25% and day-10 -∨56%) and food intake with age (day-5-∨9% and day-10 -∨48%) and instigated mitochondrial swelling and disarray in their arrangement in adult worms body-wall muscle cells. CONCLUSION: Chronic exposure to high fructose negatively impacts cell viability, mitochondrial function, basal glycolysis, and healthspan.

Extracellular electron transfer powers flavinylated extracellular reductases in Gram-positive bacteria.

Mineral-respiring bacteria use a process called extracellular electron transfer to route their respiratory electron transport chain to insoluble electron acceptors on the exterior of the cell. We recently characterized a flavin-based extracellular electron transfer system that is present in the foodborne pathogen Listeria monocytogenes, as well as many other Gram-positive bacteria, and which highlights a more generalized role for extracellular electron transfer in microbial metabolism. Here we identify a family of putative extracellular reductases that possess a conserved posttranslational flavinylation modification. Phylogenetic analyses suggest that divergent flavinylated extracellular reductase subfamilies possess distinct and often unidentified substrate specificities. We show that flavinylation of a member of the fumarate reductase subfamily allows this enzyme to receive electrons from the extracellular electron transfer system and support L. monocytogenes growth. We demonstrate that this represents a generalizable mechanism by finding that a L. monocytogenes strain engineered to express a flavinylated extracellular urocanate reductase uses urocanate by a related mechanism and to a similar effect. These studies thus identify an enzyme family that exploits a modular flavin-based electron transfer strategy to reduce distinct extracellular substrates and support a multifunctional view of the role of extracellular electron transfer activities in microbial physiology.

Sperm of Fruit Fly Drosophila melanogaster under Space Flight.

Studies of reproductive function under long-term space flight conditions are of interest in planning the exploration of deep space. Motility, including the use of various inhibitors, cellular respiration, and the content of cytoskeletal proteins were studied, assessing the level of expression of the corresponding genes in spermatozoa of Drosophila melanogaster, which were in space flight conditions for 12 days. The experiment was carried out twice on board the Russian Segment of the International Space Station. Sperm motility speed after space flight, and subsequently 16 h after landing, is reduced relative to the control by 20% (p < 0.05). In comparison with the simulation experiment, we showed that this occurs as a result of the action of overloads and readaptation to the Earth's gravity. At the same time, cellular respiration, the content of proteins of the respiratory chain, and the expression of their genes do not change. We used kinase inhibitor 6-(dimethylamino)purine (6-DMAP) and phosphatase inhibitors; 6-DMAP restored the reduced the speed of spermatozoa in the flight group to that of the control. These results can be useful in developing a strategy for protecting reproductive health during the development of other bodies in the solar system.

Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury.

Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 °C to 22 °C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 °C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury.

QcrB in Mycobacterium tuberculosis: The new drug target of antitubercular agents.

Drug-resistance in mycobacterial infections is a major global health problem that leads to high mortality and socioeconomic pressure in developing countries around the world. From finding new targets to discovering novel chemical scaffolds, there is an urgent need for the development of better approaches for the cure of tuberculosis. Recently, energy metabolism in mycobacteria, particularly the oxidative phosphorylation pathway of cellular respiration, has emerged as a novel target pathway in drug discovery. New classes of antibacterials which target oxidative phosphorylation pathway either by interacting with a protein or any step in the pathway of oxidative phosphorylation can combat dormant mycobacterial infections leading to shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one such recently discovered target of the newly approved antitubercular drug bedaquiline. Cytochrome bcc is another new target of the antitubercular drug candidate Q203, currently in phase II clinical trial. Research suggests that b subunit of cytochrome bcc, QcrB, is the target of Q203. The review article describes the structure, function, and importance of targeting QcrB throwing light on all chemical classes of QcrB inhibitors discovered to date. An understanding of the structure and function of validated targets and their inhibitors would enable the development of new chemical entities.

Electrospun Fibers Improving Cellular Respiration via Mitochondrial Protection.

Cellular respiration is the prerequisite for cell survival and functions, and mitochondrial function and microcirculation oxygen supply are essential for cellular respiration. However, in diabetic fracture, cellular respiration of bone marrow stem cells (BMSCs) is disrupted because of the dysfunction of mitochondria and microcirculation disorders. Here, the electrospun fibers of GelMA loaded with Hif-1 pathway activator (DFO) are constructed to improve the cellular respiration of BMSCs via protecting mitochondrial function and reconstructing microcirculation. The sequential process of electrospinning and UV crosslinking endowed the electrospun fibers with breathability and the biomechanical properties like the periosteum. In vitro biomolecular experiments showed that by crosslinking grafted polyethylene glycol acrylate liposomes loaded with DFO, the functional electrospun fibers can release DFO locally to activate Hif-1 in BMSCs, which can regulate the balance of Bcl-2/Bax to protect mitochondria and upregulate the expression of VEGF to reconstruct microcirculation. Animal experiments confirmed that the functional electrospun fibers can promote the recovery of diabetic fracture in vivo. These suggested that the functional electrospun fibers can improve cellular respiration for cell survival and functions of BMSCs. This study provides a new treatment strategy for diabetic fracture and other tissue regeneration on basis of cellular respiration improvement.

Prenatal acoustic programming of mitochondrial function for high temperatures in an arid-adapted bird.

Sound is an essential source of information in many taxa and can notably be used by embryos to programme their phenotypes for postnatal environments. While underlying mechanisms are mostly unknown, there is growing evidence for the involvement of mitochondria-main source of cellular energy (i.e. ATP)-in developmental programming processes. Here, we tested whether prenatal sound programmes mitochondrial metabolism. In the arid-adapted zebra finch, prenatal exposure to 'heat-calls'-produced by parents incubating at high temperatures-adaptively alters nestling growth in the heat. We measured red blood cell mitochondrial function, in nestlings exposed prenatally to heat- or control-calls, and reared in contrasting thermal environments. Exposure to high temperatures always reduced mitochondrial ATP production efficiency. However, as expected to reduce heat production, prenatal exposure to heat-calls improved mitochondrial efficiency under mild heat conditions. In addition, when exposed to an acute heat-challenge, LEAK respiration was higher in heat-call nestlings, and mitochondrial efficiency low across temperatures. Consistent with its role in reducing oxidative damage, LEAK under extreme heat was also higher in fast growing nestlings. Our study therefore provides the first demonstration of mitochondrial acoustic sensitivity, and brings us closer to understanding the underpinning of acoustic developmental programming and avian strategies for heat adaptation.

Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder, characterized by bilateral renal cyst formation. Multiple pathways are de-regulated in cystic epithelia offering good opportunities for therapy. Others and we have previously reported that metabolic reprogramming, including alterations of the TCA cycle, are prominent features of ADPKD. Several lines of evidence suggest that mitochondrial impairment might be responsible for the metabolic alterations. Here, we performed morphologic and morphometric evaluation of mitochondria by TEM in an orthologous mouse model of PKD caused by mutations in the Pkd1 gene (Ksp-Cre;Pkd1flox/- ). Furthermore, we measured mitochondrial respiration by COX and SDH enzymatic activity in situ. We found several alterations including reduced mitochondrial mass, altered structure and fragmentation of the mitochondrial network in cystic epithelia of Ksp-Cre;Pkd1flox/- mice. At the molecular level, we found reduced expression of the pro-fusion proteins OPA1 and MFN1 and up-regulation of the pro-fission protein DRP1. Importantly, administration of Mdivi-1, which interferes with DRP1 rescuing mitochondrial fragmentation, significantly reduced kidney/body weight, cyst formation, and improved renal function in Ksp-Cre;Pkd1flox/- mice. Our data indicate that impaired mitochondrial structure and function play a role in disease progression, and that their improvement can significantly modify the course of the disease.

Graduate Student Literature Review: Mitochondrial adaptations across lactation and their molecular regulation in dairy cattle.

As milk production in dairy cattle continues to increase, so do the energetic and nutrient demands on the dairy cow. Difficulties making the necessary metabolic adjustments for lactation can impair lactation performance and increase the risk of metabolic disorders. The physiological adaptations to lactation involve the mammary gland and extramammary tissues that coordinately enhance the availability of precursors for milk synthesis. Changes in whole-body metabolism and nutrient partitioning are accomplished, in part, through the bioenergetic and biosynthetic capacity of the mitochondria, providing energy and diverting important substrates, such as AA and fatty acids, to the mammary gland in support of lactation. With increased oxidative capacity and ATP production, reactive oxygen species production in mitochondria may be altered. Imbalances between oxidant production and antioxidant activity can lead to oxidative damage to cellular structures and contribute to disease. Thus, mitochondria are tasked with meeting the energy needs of the cell and minimizing oxidative stress. Mitochondrial function is regulated in concert with cellular metabolism by the nucleus. With only a small number of genes present within the mitochondrial genome, many genes regulating mitochondrial function are housed in nuclear DNA. This review describes the involvement of mitochondria in coordinating tissue-specific metabolic adaptations across lactation in dairy cattle and the current state of knowledge regarding mitochondrial-nuclear signaling pathways that regulate mitochondrial proliferation and function in response to shifting cellular energy need.

Impact of Magnetic Stimulation on Periodontal Ligament Stem Cells.

The aim of this study was to evaluate the effect of a time-dependent magnetic field on the biological performance of periodontal ligament stem cells (PDLSCs). A Western blot analysis and Alamar Blue assay were performed to investigate the proliferative capacity of magnetically stimulated PDLSCs (PDLSCs MAG) through the study of the MAPK cascade (p-ERK1/2). The observation of ALP levels allowed the evaluation of the effect of the magnetic field on osteogenic differentiation. Metabolomics data, such as oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and ATP production provided an overview of the PDLSCs MAG metabolic state. Moreover, the mitochondrial state was investigated through confocal laser scanning microscopy. Results showed a good viability for PDLSCs MAG. Magnetic stimulation can activate the ERK phosphorylation more than the FGF factor alone by promoting a better cell proliferation. Osteogenic differentiation was more effectively induced by magnetic stimulation. The metabolic panel indicated significant changes in the mitochondrial cellular respiration of PDLSCs MAG. The results suggested that periodontal ligament stem cells (PDLSCs) can respond to biophysical stimuli such as a time-dependent magnetic field, which is able to induce changes in cell proliferation and differentiation. Moreover, the magnetic stimulation also produced an effect on the cell metabolic profile. Therefore, the current study demonstrated that a time-dependent magnetic stimulation may improve the regenerative properties of PDLSCs.

Proteomics of Mouse Heart Ventricles Reveals Mitochondria and Metabolism as Major Targets of a Post-Infarction Short-Acting GLP1Ra-Therapy.

Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein-protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

Loss of Nnt Increases Expression of Oxidative Phosphorylation Complexes in C57BL/6J Hearts.

Nicotinamide nucleotide transhydrogenase (NNT) is a proton pump in the inner mitochondrial membrane that generates reducing equivalents in the form of NAPDH, which can be used for anabolic pathways or to remove reactive oxygen species (ROS). A number of studies have linked NNT dysfunction to cardiomyopathies and increased risk of atherosclerosis; however, biallelic mutations in humans commonly cause a phenotype of adrenal insufficiency, with rare occurrences of cardiac dysfunction and testicular tumours. Here, we compare the transcriptomes of the hearts, adrenals and testes from three mouse models: the C57BL/6N, which expresses NNT; the C57BL/6J, which lacks NNT; and a third mouse, expressing the wild-type NNT sequence on the C57BL/6J background. We saw enrichment of oxidative phosphorylation genes in the C57BL/B6J in the heart and adrenal, possibly indicative of an evolved response in this substrain to loss of Nnt. However, differential gene expression was mainly driven by mouse background with some changes seen in all three tissues, perhaps reflecting underlying genetic differences between the C57BL/B6J and -6N substrains.