Succinate is a key intermediate of the Krebs cycle, which has increasing recognition for its roles beyond energy metabolism, including inflammation, cellular signaling, and metabolic regulation. Extracellular succinate, in particular, has been recognized as a signaling molecule that acts via the succinate receptor 1 (SUCNR1). SUCNR1-mediated signaling, however, demonstrates significant heterogeneity across various pathological contexts, resulting in varied and occasionally contradictory biological outcomes. This complexity underscores the context-dependent characteristics of succinate signaling and its significance in disease progression. This review will offer a comprehensive analysis of the signaling pathways activated during the interaction of succinate with its receptor in various tissues, as well as the potential of succinate regulation to ameliorate several pathological conditions.

Disruption of the contact sites between mitochondria and the endoplasmic reticulum (MERCSs) adversely affects cardiomyocyte function, necessitating interventions to preserve these connections and maintain the cellular homeostasis. Currently, the nutraceutical sulforaphane (SFN) has emerged as a promising candidate for enhancing MERCSs communication and offering protection in various contexts. In this study, we investigated whether SFN preserves MERCSs functionality in cardiomyoblasts subjected to cobalt chloride (CoCl2)-induced chemical hypoxia. We explored cellular events, including oxidative stress, endoplasmic reticulum stress (ERS), and autophagy, which are regulated by MERCSs. Our findings confirmed that in rat cardiomyoblasts H9c2 pretreated with SFN and exposed to CoCl2, mitochondrial-ER associations were maintained, facilitating the formation of autophagolysosomes. This suggest that autophagy is a mechanism through which SFN protects cardiomyoblasts under chemical hypoxia. This study underscores the significance of MERCSs as functional platforms for maintaining cellular homeostasis and highlights their potential as strategic targets for mitigating the harmful effects of hypoxia in cardiomyoblasts.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by endothelial dysfunction, vascular remodeling, and a sustained increase in pulmonary vascular resistance, causing cardiopulmonary damage. The apelin receptor (APJ), a member of the G protein-coupled receptor family, has emerged as an essential modulator of vascular homeostasis. Clinical and preclinical studies have demonstrated that its activation exerts beneficial effects on the progression of PAH. Its main actions include the restoration of endothelial function, reactivation of the BMPR2/SMAD axis, induction of nitric oxide-mediated vasodilation, inhibition of autophagy and the migration of the pulmonary artery smooth muscle cells (PASMCs). Furthermore, its expression and functionality are modulated by epitranscriptomic mechanisms, particularly by microRNAs involved in the post-transcriptional regulation of key genes for vascular homeostasis. These findings position the APJ as a relevant therapeutic target in PAH. However, the clinical application of its agonists still faces pharmacokinetic limitations that restrict their therapeutic use. Therefore, the aim of this review is to gather current information on APJ in the pathophysiology of PAH and focus attention on its potential as a therapeutic target.

The study of interoganellar contactology represents a substantial advance in conceiving cells and their organelles. This presents a great challenge in terms of understanding their function and response to aging and in the development of different pathologies. This chapter will address changes in mitochondria-associated membranes (MAMs) in aging-related heart diseases, such as acute myocardial infarction and heart failure, emphasizing the role of endoplasmic reticulum stress (ERS). We also discuss the role of MAMs as possible markers of cardiovascular disease progression in geriatrician clinics, with a view to personalized therapy. Finally, we will contemplate the use of naturally occurring drugs that have been used in the experimental setting for the regulation of mitochondrial-ER communication. (119 words).

Hypercaloric intake promotes the development of obesity, a risk factor for cardiovascular disease (CVD). In recent years, it has been suggested that senescent cells have negative implications for the outcome of these chronic pathologies, and senotherapy has emerged as a novel intervention to reduce damage to the organism. However, it is unclear whether the accumulation of senescent cells induces alterations at the cardiac level in rats fed a hypercaloric diet (HD) and if the use of senotherapeutics can reverse it. To address this question, we used middle-aged female rats fed HD from 21 days to 15 months of age. Under our experimental conditions, rats exhibited cardiac hypertrophy and fibrosis, accumulation of senescent cells, changes in mitochondrial morphology, and oxidative stress. Rats were treated for 2 months with senolytic (dasatinib + quercetin, DQ) or senomorphic (sulforaphane, SFN) agents. Interestingly, the HD rats showed cardiac improvement after the treatment. Our data suggest a possible link mechanism between Nrf2 activation and mitochondria-endoplasmic reticulum contact sites (MERCSs) preservation, activated by SFN rather than by the DQ combination, which allowed cardiac structure maintenance in HD rats decreasing the harmful effects of senescent cells.

BACKGROUND:The global incidence of obesity and metabolic disorders has been associated with alterations in the central nervous system, prominently featuring increased oxidative stress and heightened production of amyloid beta peptide (AB), stemming from mitochondrial dysregulations, which potentially contribute to the onset of neurodegenerative disorders like Alzheimer disease. AIMS:In this study, we sought to ascertain whether chronic consumption of unbalanced diets by rats leads to elevated AB production and accumulation in brain structures, driving neuronal damage and mitochondrial dysfunction. METHODS:Male Wistar rats were fed with unbalanced diets rich in sucrose or lard for 12 months. Subsequently, we evaluated zoometric and biochemical parameters, including glucose tolerance, serum cholesterol, and triglycerides, alongside spatial memory. Additionally, AB accumulation, oxidative stress markers, and mitochondrial respiratory chain activity were analyzed in mitochondria and homogenates from the hippocampus and cerebral cortex. RESULTS:In our results, both dietary interventions induced abdominal obesity and spatial memory deterioration, associated to glucose metabolism disturbance, mitochondrial dysfunction, and increased oxidative stress. Nevertheless, AB accumulation was evident only in the mitochondria of rats fed with the sucrose-enriched diet. CONCLUSIONS:With these findings, we show that, although excessive consumption of fat or sucrose drives to obesity, only the last could potentially bridge the gap between obesity and neurodegenerative pathogenesis, thereby highlighting the relevance of lifestyle and diet quality, bringing a way to develop preventive strategies.

With the increase in life expectancy globally, the challenge of dealing with aging becomes more prominent. Aging is a risk factor for several diseases, including cardiovascular disease. Mitochondria, which have long been studied in relation to aging, play a crucial role in maintaining cellular homeostasis. However, there is a limitation in interorganellar communication as organisms age. The unfolded protein response in mitochondria (UPRmt) is activated during stress to maintain mitochondrial homeostasis and prevent the accumulation of damaged mitochondria. This response involves signaling from the mitochondria to the nucleus, leading to transcriptional changes. In the context of aging heart, this review explores the role of mitochondria in terms of function and morphology. It also discusses the impact of UPRmt on cardiac diseases such as heart failure, acute myocardial infarction, and dilated cardiomyopathy. The review also highlights the potential role of mitochondria-endoplasmic reticulum contact sites (MERCs) in modulating UPRmt during aging. Finally, it provides an update on molecules that induce UPRmt activity, potentially benefiting the aging heart with cardiac disease.

Metabolic syndrome (MetS) is a worldwide problem affecting at least one-third of the population. MetS patients have increased cardiovascular risk associated with an abnormal β-adrenergic response; however, it is not clear how MetS affects the cardiac β-adrenergic system. We analyzed cardiac function and the β-adrenergic response in an experimental model of MetS in rats by recording pressure–volume (PV) loops via an open-chest approach and performed a biochemical characterization of the cardiac β-adrenergic system through ELISA, radioligand binding assays, and Western blotting. Microscopy was employed to evaluate cardiac hypertrophy, fibrosis, and ultrastructure. MetS rats exhibited cardiac dysfunction, evidenced by a reduced cardiac output and ejection fraction, not explained by heart hypertrophy or fibrosis. MetS rats also had an elevated susceptibility to lethal arrhythmia following intra-cardiac administration of the non-selective β-adrenergic agonist isoproterenol, suggesting alterations in the β-adrenergic system. The total serum adrenaline and noradrenaline levels were higher in the MetS animals than those in the control group. The radioligand binding assays indicated no change in the βAR density; however, the Western blot analyses revealed decreased levels of Gαs proteins and β-arrestin 1, but increased β2AR and Gαi protein levels. This study contributes to our understanding of how MetS can alter cardiac function, raising the risk of lethal arrhythmia induced by the β-adrenergic (fight or flight) response and underscores the relevance of therapeutically targeting MetS before its pathological progression toward cardiomyopathy.

Heart failure (HF) is a heterogeneous condition that can be categorized according to the left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved (HFpEF) EF. Although HFrEF and HFpEF share some common clinical manifestations, the mechanisms underlying each phenotype are often found to be distinct. Identifying shared and divergent pathophysiological features might expand our insights on HF pathophysiology and assist the search for therapies for each HF subtype. In this study, we evaluated and contrasted two new murine models of non-ischaemic HFrEF and cardiometabolic HFpEF in terms of myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization and protein acetylation in a head-to-head fashion. We found that in conditions of similar haemodynamic stress, the HFrEF myocardium underwent a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation was greater in the HFpEF myocardium. We observed opposing features on calcium release, which was diminished in the HFrEF cardiomyocyte but enhanced in the HFpEF cardiomyocyte. Mitochondria were less polarized in both HFrEF and HFpEF cardiomyocytes, reflecting similarly impaired metabolic capacity. Hyperacetylation of cardiac proteins was observed in both models, but it was more accentuated in the HFpEF heart. Despite shared features, unique triggering mechanisms (neurohormonal overactivation in HFrEF vs. inflammation in HFpEF) appear to determine the distinct phenotypes of HF. The findings of the present research stress the need for further exploration of the differential mechanisms underlying each HF subtype, because they might require specific therapeutic interventions. KEY POINTS: The mechanisms underlying heart failure with either reduced (HFrEF) or preserved (HFpEF) ejection fraction are often found to be different. Previous studies comparing pathophysiological traits between HFrEF and HFpEF have been conducted on animals of different ages and strains. The present research contrasted two age-matched mouse models of non-ischaemic HFrEF and cardiometabolic HFpEF to uncover divergent and shared features. We found that upon similar haemodynamic stress, the HFrEF heart experienced a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation appeared to be greater in the HFpEF myocardium. Calcium release was diminished in the HFrEF cardiomyocyte and enhanced in the HFpEF cardiomyocyte. Mitochondria were comparably less polarized in both HFrEF and HFpEF myocytes. Hyperacetylation of proteins was common to both models, but stronger in the HFpEF heart. Casting light on common and distinguishing features might ease the quest for phenotype-specific therapies for heart failure patients.

Glioblastoma (GBM) is an aggressive form of cancer affecting the Central Nervous System (CNS) of thousands of people every year. Redox alterations have been shown to play a key role in the development and progression of these tumors as Reactive Oxygen Species (ROS) formation is involved in the modulation of several signaling pathways, transcription factors, and cytokine formation. The second-generation oral alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic drug used to treat of GBM, though patients often develop primary and secondary resistance, reducing its efficacy. Antioxidants represent promising and potential coadjutant agents as they can reduce excessive ROS formation derived from chemo- and radiotherapy, while decreasing pharmacological resistance. S-allyl-cysteine (SAC) has been shown to inhibit the proliferation of several types of cancer cells, though its precise antiproliferative mechanisms remain poorly investigated. To date, SAC effects have been poorly explored in GBM cells. Here, we investigated the effects of SAC in vitro, either alone or in combination with TMZ, on several toxic and modulatory endpoints—including oxidative stress markers and transcriptional regulation—in two glioblastoma cell lines from rats, RG2 and C6, to elucidate some of the biochemical and cellular mechanisms underlying its antiproliferative properties. SAC (1–750 µM) decreased cell viability in both cell lines in a concentration-dependent manner, although C6 cells were more resistant to SAC at several of the tested concentrations. TMZ also produced a concentration-dependent effect, decreasing cell viability of both cell lines. In combination, SAC (1 µM or 100 µM) and TMZ (500 µM) enhanced the effects of each other. SAC also augmented the lipoperoxidative effect of TMZ and reduced cell antioxidant resistance in both cell lines by decreasing the TMZ-induced increase in the GSH/GSSG ratio. In RG2 and C6 cells, SAC per se had no effect on Nrf2/ARE binding activity, while in RG2 cells TMZ and the combination of SAC + TMZ decreased this activity. Our results demonstrate that SAC, alone or in combination with TMZ, exerts antitumor effects mediated by regulatory mechanisms of redox activity responses. SAC is also a safe drug for testing in other models as it produces non-toxic effects in primary astrocytes. Combined, these effects suggest that SAC affords antioxidant properties and potential antitumor efficacy against GBM.

Background Previously restricted to remote areas of Central and Western Africa, the MPOX virus-based disease, also known as monkeypox, has now spread to more than 90 countries and has become endemic. As a consequence, the MPOX virus has become a global public health concern.Objective The objective of this study was to conduct a computational-multiparametric study (at the genomic and proteomic levels) of the biological sequences that express the MPOX virus envelopes in order to fathom the physicochemical regularities of these proteins.Methods Using computer programs, we determined the polarity index method (PIM) profile and protein intrinsic disorder predisposition (PIDP) for each studied protein.Results The UniProt database was able to identify sequences similar to those of the MPOX virus expressed thanks to the computational regularities found in the virus' envelope sequences.Conclusion The polarity index method and protein intrinsic disorder predisposition profiles could aid in elucidating the sequence-level structural regularities of the MPOX virus envelopes.

Mitochondrial dysfunction plays a key role in the development of neurodegenerative disorders. In contrast, the regulation of the endocannabinoid system has been shown to promote neuroprotection in different neurotoxic paradigms. The existence of an active form of the cannabinoid receptor 1 (CB1R) in mitochondrial membranes (mitCB1R), which might exert its effects through the same signaling mechanisms as the cell membrane CB1R, has been shown to regulate mitochondrial activity. Although there is evidence suggesting that some cannabinoids may induce protective effects on isolated mitochondria, substantial evidence on the role of cannabinoids in mitochondria remains to be explored. In this work, we developed a toxic model of mitochondrial dysfunction induced by exposure of brain mitochondria to the succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP). Mitochondria were also pre-incubated with the endogenous agonist anandamide (AEA) and the synthetic CB1R agonist WIN 55212–2 to evaluate their protective effects. Mitochondrial reduction capacity, reactive oxygen species (ROS) formation, and mitochondrial swelling were assessed as toxic markers. While 3-NP decreased the mitochondrial reduction capacity and augmented mitochondrial ROS formation and swelling, both AEA and WIN 55212–2 ameliorated these toxic effects. To explore the possible involvement of mitCB1R activation on the protective effects of AEA and WIN 55212–2, mitochondria were also pre-incubated in the presence of the selective CB1R antagonist AM281, which completely reverted the protective effects of the cannabinoids to levels similar to those evoked by 3-NP. These results show partial protective effects of cannabinoids, suggesting that mitCB1R activation may be involved in the recovery of compromised mitochondrial activity, related to reduction of ROS formation and further prevention of mitochondrial swelling.

Drug repurposing is defined as the use of approved therapeutic drugs for indications different from those for which they were originally designed. Repositioning diminishes both the time and cost for drug development by omitting the discovery stage, the analysis of absorption, distribution, metabolism, and excretion routes, as well as the studies of the biochemical and physiological effects of a new compound. Besides, drug repurposing takes advantage of the increased bioinformatics knowledge and availability of big data biology. There are many examples of drugs with repurposed indications evaluated in in vitro studies, and in pharmacological, preclinical, or retrospective clinical analyses. Here, we briefly review some of the experimental strategies and technical advances that may improve translational research in cardiovascular diseases. We also describe exhaustive research from basic science to clinical studies that culminated in the final approval of new drugs and provide examples of successful drug repurposing in the field of cardiology.

Cardiomyocyte senescence plays a crucial role in the pathophysiology of age-related cardiovascular disease. Senescent cells with impaired contractility, mitochondrial dysfunction, and hypertrophic growth accumulate in the heart during aging, contributing to cardiac dysfunction and remodeling. Mitochondrial dynamics is altered in aging cells, leading to changes in their function and morphology. Such rearrangements can affect the spatially restricted region of the mitochondrial membrane that interacts with reticulum membrane fragments, termed mitochondria-endoplasmic reticulum (ER) contact sites (MERCs). Besides, oxidative stress associated with inefficient organelle turnover can drive cellular senescence. Therefore, in this study, we evaluated the possible association between the senolytic effect of the antioxidant quercetin (Q) and MERCs preservation in a D-galactose-induced cellular senescence model. We found that Q ameliorates the senescent phenotype of H9c2 cells in association with increased mitochondria-ER colocalization, reduced distance between both organelles, and lower ROS production. Moreover, regulation of fusion and fission processes was related with increased mitochondrial ATP production and enhanced transmembrane potential. Overall, our data provide evidence that the inhibitory effect of Q on cellular senescence is associated with preserved MERCs and improved mitochondrial function and morphology, which might contribute to the attenuation of cardiac dysfunction.

Maternal obesity predisposes offspring (F1) to cardiovascular disease. To evaluate basal heart function and ischemia-reperfusion (IR) responses in F1 males and females of obese mothers, female Wistar rats (F0) were fed chow or an obesogenic (MO) diet from weaning through pregnancy and lactation. Non-sibling F1 males and females were weaned to chow at postnatal day (PND) 21 and euthanized at PND 550. Offspring of MO mothers (MOF1) rarely survive beyond PND 650. Hearts were immediately isolated from euthanized F1s and subjected to 30 min ischemia with 20 min reperfusion. Retroperitoneal fat, serum triglycerides, glucose, insulin, and insulin resistance were measured. Baseline left ventricular developed pressure (LVDP) was lower in male and female MOF1 than in controls. After global ischemia, LVDP in control (C) male and female F1 recovered 78 and 83%, respectively, while recovery in MO male and female F1 was significantly lower at 28 and 52%, respectively. Following the IR challenge, MO hearts showed a higher functional susceptibility to reperfusion injury, resulting in lower cardiac reserve than controls in both sexes. Female hearts were more resistant to IR. Retroperitoneal fat was increased in male MOF1 vs. CF1. Circulating triglycerides and insulin resistance were increased in male and female MOF1 vs. CF1. These data show that MO programming reduces F1 cardiac reserve associated with age-related insulin resistance in a sex-specific manner.

Obesity is a relevant health public issue and is the main factor for glucose metabolism dysregulation and diabetes progression; however, the differential role of a high-fat diet or high sugar diet consumption on glucose metabolism and insulin processing is not well understood and has been scarcely described. Our research aimed to analyze the effects of chronic consumption of both high sucrose and high-fat diets on glucose and insulin metabolism regulation. Wistar rats were fed with high-sugar or high-fat diets for 12 months; after that, fasting glucose and insulin levels were measured along with a glucose tolerance test (GTT). Proteins related to insulin synthesis and secretion were quantified in pancreas homogenates, whereas islets were isolated to analyze ROS generation and size measurement. Our results show that both diets induce metabolic syndrome, linked with central obesity, hyperglycemia, and insulin resistance. We observed alterations in the expression of proteins related with insulin synthesis and secretion, along with diminution of Langerhans islets size. Interestingly, the severity and number of alterations were more evident in the high-sugar diet than in the high-fat diet group. In conclusion, obesity and glucose metabolism dysregulation induced by carbohydrate consumption, led to worst outcomes than high-fat diet.

Background: The infection caused by the dengue fever virus is a severe threat to public health on a global scale; nevertheless, there is currently no effective medical treatment or vaccine available to prevent or treat the condition. Objective: To better understand the physicochemical regularities of these proteins, it is necessary to carry out a computational multiparametric study of the amino acid sequences of envelope proteins expressed by the dengue fever virus and obtain a bioinformatics method that can use the subsequences of the training protein group to figure out the preponderant function of a protein, up to its sequence. Methods: Essentially, at the amino acid level, various computational programs were applied to the sequences expressing the dengue virus envelope glycoproteins to determine the PIM 2.0 v profile and the Protein Intrinsic Disorder Predisposition (PIDP) profile of each protein, and then, at the nucleotide level, a set of programs for genomic analysis was applied. Finally, these results were contrasted with statistical tests. Results: The re-creation of structural morphological similarities provided by specific regularities in the PIM 2.0 v profile and PIDP of the proteins from diverse dengue fever virus envelopes made it possible to propose a computer method that employs the PIM 2.0 v profile to identify this group of proteins based on their sequences; based on our findings, this method is a "fingerprint" of this protein group. Conclusions: The typical PIM 2.0 v profiles of the dengue fever virus proteins might be reproduced by computational tools. This knowledge will be helpful in gaining a better understanding of the newly discovered virus. Moreover, the method introduced here can identify, from the sequence, the predominant function of the protein.

Caveolae-associated signaling toward mitochondria contributes to the cardioprotective mechanisms against ischemia-reperfusion (I/R) injury induced by ischemic postconditioning. In this work, we evaluated the role that the actin-cytoskeleton network exerts on caveolae-mitochondria communication during postconditioning. Isolated rat hearts subjected to I/R and to postconditioning were treated with latrunculin A, a cytoskeleton disruptor. Cardiac function was compared between these hearts and those exposed only to I/R and to the cardioprotective maneuver. Caveolae and mitochondria structures were determined by electron microscopy and maintenance of the actin-cytoskeleton was evaluated by phalloidin staining. Caveolin-3 and other putative caveolae-conforming proteins were detected by immunoblot analysis. Co-expression of caveolin-3 and actin was evaluated both in lipid raft fractions and in heart tissue from the different groups. Mitochondrial function was assessed by respirometry and correlated with cholesterol levels. Treatment with latrunculin A abolishes the cardioprotective postconditioning effect, inducing morphological and structural changes in cardiac tissue, reducing F-actin staining and diminishing caveolae formation. Latrunculin A administration to post-conditioned hearts decreases the interaction between caveolae-forming proteins, the co-localization of caveolin with actin and inhibits oxygen consumption rates in both subsarcolemmal and interfibrillar mitochondria. We conclude that actin-cytoskeleton drives caveolae signaling to mitochondria during postconditioning, supporting their functional integrity and contributing to cardiac adaption against reperfusion injury.