Search Results (212)

Platelets have long been known to be critically involved in hemostasis and thrombosis. However, platelets are also recognized as metabolically active cells that require well-regulated mitochondrial function to support their multiple functions in hemostasis, thrombosis, and inflammation. Mitochondrial activity has also recently been shown to play a crucial role in determining platelet activation, survival, and pro-inflammatory potential. A key nexus in these processes is the mitochondrial permeability transition pore (mPTP), a high-conductance channel in the inner mitochondrial membrane. Sustained mPTP opening triggers mitochondrial depolarization, the cessation of ATP synthesis, osmotic swelling, and, finally, platelet dysfunction or clearance. However, its transient opening might play physiological signaling roles. This review summarizes the current understanding of the molecular components and regulatory factors governing the platelet mPTP, explores its physiological and pathological relevance, and evaluates its potential as a therapeutic target in cardiovascular disease, inflammation, cancer, and potentially neurodegenerative diseases. We also highlight the ongoing challenges and crucial future directions in deciphering the complexities of platelet mitochondrial dynamics and mPTP functions. Full article

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson’s disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation. Full article

Inorganic polyphosphate (polyP) is an evolutionarily conserved polymer that has recently gained relevance in neuronal physiology and pathophysiology. Although its roles, such as mitochondrial bioenergetics, calcium homeostasis, and the oxidative stress response, for example, are increasingly recognized, its specific implications in neurological disorders remain underexplored. This review focuses on synthesizing the current knowledge of polyP in the context of central nervous system (CNS) diseases, highlighting how its involvement in key mitochondrial processes may influence neuronal survival and function. In particular, we examine recent evidence linking polyP to mechanisms relevant to neurodegeneration, such as the modulation of the mitochondrial permeability transition pore (mPTP), regulation of amyloid fibril formation, and oxidative stress responses. In addition, we analyze the emerging roles of polyP in inflammation and related cell signaling in CNS disorders. By organizing the existing data around the potential pathological and protective roles of polyP in the CNS, this review identifies it as a candidate of interest in the context of neurodegenerative disease mechanisms. We aim to clarify its relevance and stimulate future research on its molecular mechanisms and translational potential. Full article

Nitric oxide (NO) has a dual effect on mitochondria. Incubating liver mitochondria with NO improves oxidative phosphorylation (OXPHOS) efficiency by decreasing state 4 respiration more than ATP synthesis and preventing mitochondrial permeability transition pore (mPTP) opening. We evaluated the effect of L-arginine (L-arg), an NO donor, on isolated liver mitochondrial respiration and mPTP in sepsis. Male mice were subjected to cecal ligation and perforation (CLP) with saline resuscitation or sham. After 8, 24, and 48 h, with and without L-arg, we measured isolated liver mitochondrial respiration and cytochrome c oxidase (COX) activity using polarographic methods and calcium retention capacity (CRC) to assess the mPTP and NO metabolites via the Griess reaction. Mitochondrial NO synthase (mtNOS) was identified by Western blot. CLP decreased state 3 respiration at 24 and 48 h, decreased COX activity at 8, 24, and 48 h, and increased state 4 respiration and decreased the respiratory control ratio (RCR) and CRC at 48 h. L-arg increased NO levels at 8 h, decreased state 4 respiration more than state 3 respiration (−39% versus −12%) at 48 h, decreased the CRC in the CLP groups at 24 and 48 h, but did not improve RCR. Our data suggests that L-arg does not restore liver mitochondrial OXPHOS efficiency or prevent mPTP opening in the late or recovery phases of sepsis. Full article

The study of metabolic abnormalities regarding mitochondrial respiration and energy production has significantly advanced our understanding of cell biology and molecular mechanisms underlying cardiovascular diseases (CVDs). Mitochondria provide 90% of the energy required for maintaining normal cardiac function and are central to heart bioenergetics. During the initial phase of heart failure, mitochondrial number and function progressively decline, causing a decrease in oxidative metabolism and increased glucose uptake and glycolysis, leading to ATP depletion and bioenergetic starvation, finally contributing to overt heart failure. Compromised mitochondrial bioenergetics is associated with vascular damage in hypertension, vascular remodeling in pulmonary hypertension and acute cardiovascular events. Thus, mitochondrial dysfunction, leading to impaired ATP production, excessive ROS generation, the opening of mitochondrial permeability transition pores and the activation of apoptotic and necrotic pathways, is revealed as a typical feature of common CVDs. Molecules able to positively modulate cellular metabolism by improving mitochondrial bioenergetics and energy metabolism and inhibiting oxidative stress production are expected to exert beneficial protective effects in the heart and vasculature. This review discusses recent advances in cardiovascular research through the study of cellular bioenergetics in both chronic and acute CVDs. Emerging therapeutic strategies, specifically targeting metabolic modulators, mitochondrial function and quality control, are discussed. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

Background: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new generation of MDR inhibitors with high affinity to ABC proteins. However, there are still no data on the possible effect of Tq on mitochondria as an important target in the regulation of cell death or survival. Methods: We investigated the influence of Tq on the Ca²⁺-dependent mitochondrial permeability transition pore (mPTP). The effect of Tq was assessed using several parameters, including the calcium load, membrane potential, and mitochondrial swelling. To evaluate the specific targets of Tq, selective inhibitors of components of the mitochondrial pore were used, including adenine nucleotides, carboxyatractylozide (Catr) and bongkrekic acid (BA), oligomycin, and cyclosporine A. Results: Tq decreased the calcium retention capacity, activated mitochondrial swelling, and lowered the influence of ADP and ATP, the inhibitors of the Ca²⁺-induced pore opening, at their low concentrations. These effects of Tq were observed in both calcium-load and swelling assays, thus mimicking the effect of Catr, a selective inhibitor of adenine nucleotide translocase (ANT). Tq also decreased the protective effect of BA, an inhibitor of ANT and mPTP, on the calcium retention capacity of mitochondria. Further, Tq dose-dependently decreased the inhibitory effect of a low ATP concentration but not of high concentrations, at which the effect of Tq was activated by oligomycin, an inhibitor of F-ATP synthase. Conclusions: The influence of Tq extends to mitochondria, specifically to the regulation of membrane permeability, promoting the activation of pore opening, probably through an interaction with ANT, a component of the pore-forming complex. The effect of Tq on the opening of mPTP is strongly dependent on the concentrations of adenine nucleotides and, consequently, on the functional state of mitochondria. The direct influence of Tq on mitochondria can be considered as a new activity that promotes the sensitization of cells to various treatments and stimuli. Full article

Bcl-2-like protein 13 (Bcl2l13) plays an important role in the cell apoptosis and mitochondrial autophagy of mammals. However, the role of bcl2l13 remains unclear in fish. Therefore, in this study, the function of Megalobrama amblycephala bcl2l13 gene in apoptosis and autophagy was investigated. The results showed that the overexpression of M. amblycephala bcl2l13 under hypoxic condition led to a reduction of reactive oxygen species (ROS), an increase in the expression levels of autophagy-related genes (p62, lc3, pink1), and a disruption of mitochondrial structure. However, deleting its transmembrane (TM) and Bcl-2 homology no (BHNo) domains decreased the P62 protein level, suggesting its essential role in autophagy. Furthermore, bcl2l13 overexpression inhibited cell proliferation and increased apoptosis. Additional studies revealed that the permeability of the mitochondrial permeability transition pore (mPTP) increased after overexpression of bcl2l13, but decreased upon deletion of the TM domain. Additionally, hypoxia led to elevated Bcl2l13 and P62 levels, and caused mitochondrial damage in M. amblycephala liver after 48 h of treatment. In conclusion, bcl2l13 may induce autophagy, inhibit cell proliferation and promote apoptosis, while its TM and BHNo domains play pivotal roles in these processes. Full article

Increased acetylation or “hyperacetylation” of mitochondrial (MITO) proteins can lead to abnormalities of the electron transport chain (ETC) and oxidative phosphorylation. In this study we examined the levels of proteins that regulate acetylation. Studies were performed in isolated MITO fractions from left ventricular (LV) myocardium of seven healthy normal (NL) dogs and seven dogs with coronary microembolization-induced heart failure (HF, LV ejection fraction ~35%). Protein levels of drivers of hyperacetylation, namely sirtuin-3 (Sirt-3), a MITO deacetylase, and CD38, a regulator of nicotinamide adenine dinucleotide (NAD⁺), were measured by Western blotting, and the bands were quantified in densitometric units (du). To assess MITO function, MITO components directly influenced by a hyperacetylation state, namely the protein level of cytophillin-D (CyPD), a regulator of MITO permeability transition pore and MITO Complex-I activity, were also measured. Protein level of Sirt-3 and amount of NAD⁺ were decreased in HF compared to NL dogs. Protein levels of CD38 and CyPD were increased in HF compared to NL dogs. Complex-I activity was decreased in HF compared to NL dogs. The results support the existence of a protein hyperacetylation state in mitochondria of failing LV myocardium compared to NL. This abnormality can contribute to MITO dysfunction as evidenced by reduced Complex-I activity and opening of MITO permeability pores. Full article

Chemotherapeutic agents play a crucial role in cancer treatment. However, their use is often associated with significant adverse effects, particularly cardiotoxicity. Drugs such as anthracyclines (e.g., doxorubicin) and platinum-based agents (e.g., cisplatin) cause mitochondrial damage, which is one of the main mechanisms underlying cardiotoxicity. These drugs induce oxidative stress, leading to an increase in reactive oxygen species (ROS), which in turn damage the mitochondria in cardiomyocytes, resulting in impaired cardiac function and heart failure. Mitochondria-targeted antioxidants (MTAs) have emerged as a promising cardioprotective strategy, offering a potential solution. These agents efficiently scavenge ROS within the mitochondria, protecting cardiomyocytes from oxidative damage. Recent studies have shown that MTAs, such as elamipretide, SkQ1, CoQ10, and melatonin, significantly mitigate chemotherapy-induced cardiotoxicity. These antioxidants not only reduce oxidative damage but also help maintain mitochondrial structure and function, stabilize mitochondrial membrane potential, and prevent excessive opening of the mitochondrial permeability transition pore, thus preventing apoptosis and cardiac dysfunction. In this review, we integrate recent findings to elucidate the mechanisms of chemotherapy-induced cardiotoxicity and highlight the substantial therapeutic potential of MTAs in reducing chemotherapy-induced heart damage. These agents are expected to offer safer and more effective treatment options for cancer patients in clinical practice. Full article

The effect of the gut microbiota extends beyond their habitant place from the gastrointestinal tract to distant organs, including the cardiovascular system. Research interest in the relationship between the heart and the gut microbiota has recently been emerging. The gut microbiota secretes metabolites, including Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids (BAs), indole propionic acid (IPA), hydrogen sulfide (H₂S), and phenylacetylglutamine (PAGln). In this review, we explore the accumulating evidence on the role of these secreted microbiota metabolites in the pathophysiology of ischemic and non-ischemic heart failure (HF) by summarizing current knowledge from clinical studies and experimental models. Elevated TMAO contributes to non-ischemic HF through TGF-ß/Smad signaling-mediated myocardial hypertrophy and fibrosis, impairments of mitochondrial energy production, DNA methylation pattern change, and intracellular calcium transport. Also, high-level TMAO can promote ischemic HF via inflammation, histone methylation-mediated vascular fibrosis, platelet hyperactivity, and thrombosis, as well as cholesterol accumulation and the activation of MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell myocardial infiltration, and HDAC 5 and 6 activities, leading to non-ischemic HF, while reactive oxygen species production and the hyperactivation of caveolin-ACE axis result in ischemic HF. An altered BAs level worsens contractility, opens mitochondrial permeability transition pores inducing apoptosis, and enhances cholesterol accumulation, eventually exacerbating ischemic and non-ischemic HF. IPA, through the inhibition of nicotinamide N-methyl transferase expression and increased nicotinamide, NAD+/NADH, and SIRT3 levels, can ameliorate non-ischemic HF; meanwhile, H₂S by suppressing Nox4 expression and mitochondrial ROS production by stimulating the PI3K/AKT pathway can also protect against non-ischemic HF. Furthermore, PAGln can affect sarcomere shortening ability and myocyte contraction. This emerging field of research opens new avenues for HF therapies by restoring gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation and as such normalizing circulating levels of TMAO, SCFA, BAs, IPA, H₂S, and PAGln. Full article

Coccidiosis in chickens is a parasitic disease caused by Eimeria species, resulting in significant economic losses to the poultry industry. Among these species, Eimeria tenella is considered the most virulent pathogen, with its infection strongly associated with the apoptotic response of host cells. Eimeria tenella modulates host cell apoptosis in a stage-specific manner, suppressing apoptosis in the early phase to promote its intracellular development and triggering apoptosis in later stages to facilitate parasite egress and disease progression. This study established an in vitro infection model using 60 fifteen-day-old chick embryo cecal epithelial cells and infecting the cells with Eimeria tenella sporozoites at a 1:1 ratio of host cells to sporozoites. The aim was to examine the relationship between parasitic infection and the apoptotic response of host cells in the chick embryo cecal epithelial cells infected with E. tenella. The roles of the mitochondrial permeability transition pore (MPTP) and cytochrome c in intrinsic apoptosis were examined through the application of cyclosporine A (CsA), N, N, N’, N’-tetramethyl-1,4-phenylenediamine (TMPD), and ascorbate (Asc). TUNEL staining, ELISA, and flow cytometry were performed to evaluate apoptotic rates. CsA, TMPD, and Asc significantly (p < 0.01) decreased cytochrome c release, caspase-9 activation, and apoptotic rates from 24 to 120 h post-E. tenella infection. These findings highlight the significance of cytochrome c-mediated, mitochondria-dependent apoptotic pathways in parasitized chick embryo cecal epithelial cells. Full article

Lipid emulsion has recently emerged as an effective agent for improving the cardiotoxicity of highly lipophilic drugs. However, its effect on cardiotoxicity induced by labetalol, a nonselective beta-blocker, remains unknown. In this study, we investigated the effects of lipid emulsion on the cardiotoxicity of labetalol in rat cardiomyoblasts and tried to decipher the underlying mechanisms. The effects of lipid emulsion on labetalol-induced changes in cell viability, expression of Bax/Bcl-2, cleaved caspase-3, and cleaved caspase-9, and phosphorylation of GSK-3β, Akt, and PI3K were examined. Lipid emulsion inhibited labetalol-induced decrease in cell viability, whereas LY294002, MK2206, and SB216763, the inhibitors of phosphoinositide 3-kinase (PI3K), Akt, glycogen synthase kinase-3β (GSK-3β), respectively, partially attenuated this restoration of cell viability. Lipid emulsion reversed the increase in expression of cleaved caspase-3, cleaved caspase-9, and Bax/Bcl-2 and decrease in the phosphorylation of GSK-3β, Akt, and PI3K by labetalol. Lipid emulsion and cyclosporin, a mitochondrial permeability transition pore (MPTP) inhibitor, reduced the labetalol-induced increase in the number of TUNEL-positive cells and promoted late-stage apoptosis. Overall, lipid emulsion inhibited apoptotic cell death caused by labetalol toxicity via the inhibition of intrinsic apoptotic pathway and MPTP in rat cardiomyoblasts, which appears to involve PI3K, Akt, and GSK-3β signaling pathways. Full article

Mitochondrial homeostasis is crucial for maintaining cellular energy production and preventing oxidative stress, which is essential for overall cellular function and longevity. Mitochondrial damage and dysfunction often occur concomitantly in myocardial ischemia–reperfusion injury (MIRI). Notoginsenoside R1 (NGR1), a unique saponin from the traditional Chinese medicine Panax notoginseng, has been shown to alleviate MIRI in previous studies, though its precise mechanism remains unclear. This study aimed to elucidate the mechanisms of NGR1 in maintaining mitochondrial homeostasis in hypoxia/reoxygenation (H/R) H9c2 cells. The results showed that NGR1 pretreatment effectively increased cell survival rates post-H/R, reduced lactate dehydrogenase (LDH) leakage, and mitigated cell damage. Further investigation into mitochondria revealed that NGR1 alleviated mitochondrial structural damage, improved mitochondrial membrane permeability transition pore (mPTP) persistence, and prevented mitochondrial membrane potential (Δψm) depolarization. Additionally, NGR1 pretreatment enhanced ATP levels, increased the activity of mitochondrial respiratory chain complexes I–V after H/R, and reduced excessive mitochondrial reactive oxygen species (mitoROS) production, thereby protecting mitochondrial function. Further analysis indicated that NGR1 upregulated the expression of mitochondrial biogenesis-related proteins (PGC-1α, Nrf1, Nrf2) and mitochondrial fusion proteins (Opa1, Mfn1, Mfn2), while downregulating mitochondrial fission proteins (Fis1, Drp1) and reducing mitochondrial autophagy (mitophagy) levels, as well as the expression of mitophagy-related proteins (Pink1, Parkin, BNIP3) post-H/R. Therefore, this study showed that NGR1 can maintain mitochondrial homeostasis by regulating mitophagy, mitochondrial fission–fusion dynamics, and mitochondrial biogenesis, thereby alleviating H9c2 cell H/R injury and protecting cardiomyocytes. Full article

Background. Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown. In vitro experiments showed that AcP is a powerful agent of nonenzymatic acetylation of proteins. The influence of AcP on isolated mitochondria has not been previously studied. Methods. In this work, we tested the influence of AcP on the opening of the mitochondrial permeability transition pore (mPTP), respiration, and succinate dehydrogenase (SDH) activity under neutral and alkaline conditions stimulating the nonenzymatic acetylation using polarographic, cation-selective, and spectrophotometric methods. Results. It was found that AcP slowed down the opening of the mPTP by calcium ions and decreased the efficiency of oxidative phosphorylation and the activity of SDH. These effects were observed only at neutral pH, whereas alkaline pH by itself caused a decrease in these functions to a much greater extent than AcP. AcP at a concentration of 0.5–1 mM decreased the respiratory control and the swelling rate by 20–30%, while alkalization decreased them twofold, thereby masking the effect of AcP. Presumably, the acetylation of adenine nucleotide translocase involved in both the opening of mPTP and oxidative phosphorylation underlies these changes. The intermediate electron carrier phenazine methosulfate (PMS), removing SDH inhibition at the ubiquinone-binding site, strongly activated SDH under alkaline conditions and, partially, in the presence of AcP. It can be assumed that AcP weakly inhibits the oxidation of succinate, while alkalization slows down the electron transfer from the substrate to the acceptor. Conclusions. The results show that both AcP and alkalization, by promoting nonmetabolic and nonenzymatic acetylation from the outside, retard mitochondrial functions. Full article