Cellular Bioenergetics Research Articles

Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice.

Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disorder, characterised by progressive immobility, chronic inflammation and premature death, is caused by the loss of the mechano-transducing signalling molecule, dystrophin. In non-contracting cells, such as neurons, dystrophin is likely to have a functional role in synaptic plasticity, anchoring post-synaptic receptors. Dystrophin-expressing hippocampal neurons are key to cognitive functions such as emotions, learning and the consolidation of memories. In the context of disease-induced chronic inflammation, we have explored the role of the pleiotropic cytokine, interleukin (IL)-6 in hippocampal dysfunction using immunofluorescence, electrophysiology and metabolic measurements in dystrophic mdx mice. Hippocampal long-term potentiation (LTP) of the Schaffer collateral-CA1 projections was suppressed in mdx slices. Given the importance of mitochondria-generated ATP in synaptic plasticity, reduced maximal respiration in the CA1 region may impact upon this process. Consistent with a role for IL-6 in this observation, early LTP was suppressed in dystrophin-expressing wildtype slices exposed to IL-6. In dystrophic mdx mice, exposure to IL-6 suppressed mitochondrial-mediated basal metabolism in CA1, CA3 and DG hippocampal regions. Furthermore, blocking IL-6-mediated signalling by administering neutralising monoclonal IL-6 receptor antibodies intrathecally, normalised LTP in mdx mice. The impact of dystrophin loss from the hippocampus was associated with modified cellular bioenergetics, which underpin energy-driven processes such as the induction of LTP. The additional challenge of pathophysiological levels of IL-6 resulted in altered cellular bioenergetics, which may be key to cognitive deficits associated with the loss of dystrophin.

Abstract TP386: Impaired Bioenergetics in the Aging Cerebral Microvasculature: Effect of Angiotensin-(1-7) or Alamandine

Background: Aging increases risk for the development of vascular cognitive impairment and dementia (VCID). Impaired bioenergetics, mitochondrial oxidative phosphorylation (OxPhos) and glycolysis, in the brain microvascular endothelium induce neurovascular uncoupling, which is one of the underlying mechanisms of VCID. Angiotensin (Ang)-(1-7) and Alamandine (Ala) are vascular protective peptides of renin angiotensin system. Ang-(1-7) is generated by angiotensin-converting enzyme-2 (ACE2) from Ang II, and produces vascular protective effects by acting on Mas receptor (MasR). Ala has been shown to be derived from Ang A by ACE2 or from Ang-(1-7) by an enzyme, which is yet to be characterized, with decarboxylase activity or Mas related G-protein-coupled receptor, member D (MrgD), respectively. This study evaluated the effect of aging on cellular bioenergetics in brain microvasculature (BMV) and tested the potential beneficial effects of Ang-(1-7) or Ala. Methods: BMVs were obtained from Young (Y) and Old (O) mice of age 3 - 4 and 22 – 24 months, respectively, by using ultracentrifugation method. Protein expression of receptors or mitochondrial complexes in BMVs were evaluated by western blotting. Seahorse bioanalyzer was used to determine OxPhos and glycolysis in BMVs. Results: Expression of MasR or MrgD was higher in the O-BMVs compared to the Young ( P < 0.05, n = 4). Expression of mitochondrial respiratory complex proteins, II, IV and V, was lower in the O-BMVs (vs Y-BMVs, P < 0.05, n = 4). MitoStress test revealed that the basal and maximal respiration, and the spare capacity are lower in the O-BMVs compared to the Y-BMVs ( P < 0.05). Ang-(1-7) or Ala (100 nM) increased the basal and maximal respiration, spare capacity and ATP production in the O-BMVs compared to the untreated ( P < 0.05). Glycolysis rate assay (GRA) showed that basal glycolysis and basal proton efflux rate were lower in the O-BMVs ( P < 0.01 vs Y-BMVs) that were increased by Ang-(1-7) or Ala. Conclusion: The study shows that aging is associated with impaired cellular bioenergetics in the brain microvasculature and that the angiotensin peptides, Ang-(1-7) or Ala, restore the bioenergetics therefore have the potential to reverse neurovascular uncoupling in aging.

Naltriben promotes tumor growth by activating the TRPM7-mediated development of the anti-inflammatory M2 phenotype

Macrophage plasticity is critical for maintaining immune function and developing solid tumors; however, the macrophage polarization mechanism remains incompletely understood. Our findings reveal that Mg2+ entry through distinct plasma membrane channels is critical to macrophage plasticity. Naïve macrophages displayed a previously unidentified Mg2+ dependent current, and TRPM7-like activity, which modulates its survival. Significantly, in M1 macrophages, Mg2+ entry is facilitated by a novel Mg²-dependent current that relies on extracellular Mg2+, which was crucial for activating iNOS/NFκB pathways and cellular bioenergetics, which drives pro-inflammatory cytokines. Conversely, in M2 macrophages, Mg2+ entry occurs primarily through TRPM7 channels, pivotal for IL-4 and IL-10-mediated anti-inflammatory cytokine secretion. Notably, the Mg2+ deficient diet or addition of TRPM7 agonist Naltriben suppresses the M1 phenotype while promoting angiogenic factors and fostering tumor growth. These findings suggest that Mg2+ flux via specific channels is indispensable for macrophage polarization, with its dysregulation playing a pivotal role in tumor progression.

Improved Black Phosphorus Nanocomposite Hydrogel for Bone Defect Repairing: Mechanisms for Advancing Osteogenesis.

Bone defects caused by fractures and diseases often do not heal spontaneously. They require external agents for repair and regeneration. Bone tissue engineering is emerging as a promising alternative to traditional therapies like autografts and allografts. Nanobiomaterials enhance osteoblast resistance to harsh environments by promoting cell differentiation. Black phosphorus (BP), a novel 2D material in biomedicine, displays unique osteogenic and antimicrobial properties. However, BP nanosheets still face clinical limitations like rapid degradation and high-dose cytotoxicity. To address these, the introduction of amino-silicon phthalocyanine (SiPc-NH2) is investigated to see if it can enhance BP dispersion, reduce BP oxidation, and improve stability and safety for better osteogenesis and antibacterial effects through noncovalent interactions (van der Waals, π-π stacking and electrostatic interactions). Here, the self-healing hydrogel is successfully designed using a step-by-step co-assembly of BP and SiPc-NH2. SiPc-NH2 as a "structural stabilizer" of BP nanosheets reconstructed well-dispersed BP-SiPc-NH2 nanosheets, which improves the biocompatibility of BP, reduces oxidation and enhances photothermal conversion, guaranteeing osteogenic and antimicrobial properties. Furthermore, findings show BP-SiPc-NH2-induced mitochondrial changes support osteogenesis by regulating the crosstalk between Hippo and Wnt signaling pathways-mediated mitochondrial homeostasis, and boosting cellular bioenergetics. Overall, this mitochondrial morphology-based BP-SiPc-NH2 strategy holds great promise for bone repair applications.

Photodynamic therapy photosensitizers and photoactivated chemotherapeutics exhibit distinct bioenergetic profiles to impact ATP metabolism.

Energy is essential for all life, and mammalian cells generate and store energy in the form of ATP by mitochondrial (oxidative phosphorylation) and non-mitochondrial (glycolysis) metabolism. These processes can now be evaluated by extracellular flux analysis (EFA), which has proven to be an indispensable tool in cell biology, providing previously inaccessible information regarding the bioenergetic landscape of cell lines, complex tissues, and in vivo models. Recently, EFA demonstrated its utility as a screening tool in drug development, both by providing insights into small molecule-organelle interactions, and by revealing the peripheral and potentially undesired off-target effects small molecules have within cells. Surprisingly, technologies to quantify cellular bioenergetics have not been systematically applied in phototherapy development, leaving open several questions about how the mechanism of action of a compound can impact essential cellular functions. Here, we utilized the Seahorse analyzer to address this question for photosensitizers (PSs) for photodynamic therapy (PDT) and contrast these systems to molecules that photo-release a ligand and thus act as photocages or photoactivated chemotherapeutics (PACT), intending to understand the influence these two classes of compounds have on cellular bioenergetics. EFA results show that acute treatment of A549 lung adenocarcinoma cells with PDT agents induces a quiescent bioenergetic response as a result of mitochondrial respiration shutdown. The loss of oxidative phosphorylation is followed by disruption of glycolysis, which occurs after an initial increase in glycolytic respiration is unable to compensate for the interruption of the electron transport chain (ETC). In contrast, the PACT agents tested had little impact on cellular respiration, and the minor inhibition of these metabolic processes was not related to the mechanism of action, as reflected by a lack of correlation with photoejection efficiency. Notably, a system capable of both generating 1O2 and photo-releasing a ligand exhibited the dominant profile of a PDT agent and induced the quiescent bioenergetic state, indicating potential implications on cellular bioenergetics for so-called dual-action agents. These findings are presented with the aim to provide the necessary groundwork for expanding the application and utility of EFA to phototherapeutics and to highlight the role of metabolic alterations in PDT.

Emodin disrupts the KITENIN oncogenic complex by binding ErbB4 and suppresses colorectal cancer progression in dual blockade with KSRP-binding compound

BackgroundThe KITENIN/ErbB4 complex has been reported to participate in metastasis, which is the principal reason of death in most colorectal cancer patients. PurposeNew therapeutics need to be developed to suppress the malignant effects of the KITENIN/ErbB4 complex, which is related to drug resistance. The present study aimed to evaluate changes in cancer cell invasion capacity, transcriptional regulators, and cellular bioenergetics after targeting the KITENIN/ErbB4 complex with emodin. Moreover, we aimed to reveal the mechanistic effects of emodin and observe the dual blockade effects of ErbB4-targeted therapy with KH-type splicing regulatory protein (KSRP) and search for new alternative blockade pathways. MethodsUsing in vitro, in vivo, molecular-docking, and metabolomics studies, we evaluated the anticancer effect of emodin alone or in combination with DKC-C14S. ResultsEmodin treatment decreased KITENIN and ErbB4 protein levels. The dysfunctional KITENIN/ErbB4 complex suppressed KITENIN-mediated cell invasion and downregulated AP-1 activity, aerobic glycolysis, and the levels of transcriptional regulators associated with cell metabolism. We conclude that emodin targets the KITENIN/ErbB4 complex and offering a novel mechanism by which it disrupts KITENIN-mediated signaling. Furthermore, we were demonstrated that the dual blocking effect of emodin and DKC-14S on the KITENIN complex showed synergistic effects in suppressing colorectal cancer progression under in cell-based and animal assay. ConclusionThe results suggest that co-treatment with ErbB4 and KSRP-binding compounds could constitute a potential strategy for the control colorectal cancer progression by disrupting the KITENIN complex.

Subcellular mitochondrial heterogeneity enables opposing metabolic demands.

Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.

Insights on Bmi-1 therapeutic targeting in head and neck cancers.

The B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) protein of the polycomb complex is an essential mediator of the epigenetic transcriptional silencing by the chromatin structure. It has been reported to be crucial for homeostasis of the stem cells and tumorigenesis. Though years of investigation have clarified Bmi-1's transcriptional regulation, post-translational modifications, and functions in controlling cellular bioenergetics, pathologies, and DNA damage response, the full potential of this protein with so many diverse roles are still unfulfilled. Bmi-1 is overexpressed in many human malignancies. Unraveling the Bmi-1's precise functional role in head and neck cancers can be attractive for mechanisms-based developmental therapeutics. This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on the role that Bmi-1 plays in oral cancer progression and evaluates how this can be used in advancing clinical treatment strategies for head and neck cancer. Bmi-1 is a promising target for therapy because it has been linked to a stemness and oncogenesis signature. However, to use Bmi-1 as a prognostic marker and a therapeutic target in the long run, new methods are imperative for further characterization of the physiological roles of Bmi-1. Current biological insights of Bmi-1 as a master regulator of stem cell self-renewal have emerged as a prominent player in cancer stem cell (CSC) biology. Bmi-1+ cells mediate chemoresistance and metastasis. On the other hand, inhibiting Bmi-1 rescinds CSC function and re-sensitizes cancer cells to chemotherapy. Therefore, elucidating therapeutic approaches targeting Bmi-1 can be leveraged to further research analysis to advance clinical treatment strategies for head and neck cancer.

Circadian clockwork controls the balance between mitochondrial turnover and dynamics: What is life … without time marking?

Circadian rhythms driven by biological clocks regulate physiological processes in all living organisms by anticipating daily geophysical changes, thus enhancing environmental adaptation. Time-resolved serial multi-omic analyses in vivo, ex vivo, and in synchronized cell cultures have revealed rhythmic changes in the transcriptome, proteome, and metabolome, involving up to 50% of the mammalian genome. Mitochondrial oxidative metabolism is central to cellular bioenergetics, and many nuclear genes encoding mitochondrial proteins exhibit both circadian and ultradian oscillatory expression. However, studies on mitochondrial DNA (mtDNA) gene expression remain incomplete. Using a well-established in vitro synchronization protocol, we investigated the time-resolved expression of mtDNA genes coding for respiratory chain complex subunits, revealing a rhythmic profile dependent on BMAL1, the master circadian clock transcription factor. Additionally, the expression of genes coding for key mitochondrial biogenesis transcription factors, PGC1a, NRF1, and TFAM, showed BMAL1-dependent circadian oscillations. Notably, LC3-II, involved in mitophagy, displayed a similar in-phase circadian expression, thereby maintaining stable respiratory chain complex levels. Moreover, we found that simultaneous mitochondrial biogenesis and degradation occur in a coordinated manner with cycles in organelle dynamics, leading to rhythmic changes in mitochondrial fission and fusion. This study provides new insights into circadian clock regulation of mitochondrial turnover, emphasizing the importance of temporal regulation in cellular metabolism. Understanding these mechanisms opens potential therapeutic avenues for targeting mitochondrial dysfunctions and related metabolic disorders.

α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.

Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.

GPR68 Mediates Lung Endothelial Dysfunction Caused by Bacterial Inflammation and Tissue Acidification.

Tissue acidification resulting from dysregulated cellular bioenergetics accompanies various inflammatory states. GPR68, along with other members of proton-sensing G protein-coupled receptors, responds to extracellular acidification and has been implicated in chronic inflammation-related diseases such as ischemia, cancer, and colitis. The present study examined the role of extracellular acidification on human pulmonary endothelial cell (EC) permeability and inflammatory status per se and investigated potential synergistic effects of acidosis on endothelial dysfunction caused by bacterial lipopolysaccharide (LPS, Klebsiella pneumoniae). Results showed that medium acidification to pH 6.5 caused a delayed increase in EC permeability illustrated by a decrease in transendothelial electrical resistance and loss of continuous VE-cadherin immunostaining at cell junctions. Likewise, acidic pH induced endothelial inflammation reflected by increased mRNA and protein expression of EC adhesion molecules VCAM-1 and ICAM-1, upregulated mRNA transcripts of tumor necrosis factor-α, IL-6, IL-8, IL-1β, and CXCL5, and increased secretion of ICAM-1, IL-6, and IL-8 in culture medium monitored by ELISA. Among the GPCRs tested, acidic pH selectively increased mRNA and protein expression of GPR68, and only the GPR68-specific small molecule inhibitor OGM-8345 rescued acidosis-induced endothelial permeability and inflammation. Furthermore, acidic pH exacerbated LPS-induced endothelial permeability and inflammatory response in cultured lung macrovascular as well as microvascular endothelial cells. These effects were suppressed by OGM-8345 in both EC types. Altogether, these results suggest that GPR68 is a critical mediator of acidic pH-induced dysfunction of human pulmonary vascular endothelial cells and mediates the augmenting effect of tissue acidification on LPS-induced endothelial cell injury.

Fucoxanthin alleviates the cytotoxic effects of cadmium and lead on a human osteoblast cell line.

Cadmium (Cd) and lead (Pb) are non-biodegradable heavy metals (HMs) that persistently contaminate ecosystems and accumulate in bones, where they exert harmful effects. This study aimed to investigate the protective effect of fucoxanthin (FX) against the chemical toxicity induced by Cd and Pb in human bone osteoblasts in vitro, using various biochemical and molecular assays. The effect of metals and FX on osteoblasts viability was assayed by MTT, then the effect of Pb, Cd, and FX on the cells' mitochondrial parameters was studied via assays for ATP, mitochondrial membrane potential (MMP), mitochondrial complexes, and lactate production. Also, the effect of metals on oxidative stress was assessed by reactive oxygen species, lipid peroxidation and antioxidant enzymes assays. Also the effect of FX and metals on apoptosis caspases and related genes was assessed. When Cd and Pb were added to human osteoblast cultures at concentrations ranging from 1-20μM for 72h, they significantly reduced osteoblast viability in a time and concentration-dependent manner. The cytotoxic effect of Cd on osteoblasts was greater than that of Pb, with estimated EC50 of 8 and 12μM, respectively, after 72h of exposure. FX (10 and 20μM) alleviated the cytotoxicity of the metals. Bioenergetics assays, including ATP, MMP, and mitochondrial complexes I and III activities, revealed that HMs at 1 and 10μM concentrations inhibited cellular bioenergetics after 72h of exposure. Cd and Pb also increased lipid peroxidation and reactive oxygen species while reducing catalase and superoxide dismutase antioxidant activities and oxidative stress-related genes. This was accompanied by increased caspases -3, -8, and-9 and Bax/bCl-2 ratio. Co-treatment with FX (10 and 20μM) mitigated the disruption of bioenergetics, oxidative damage, and apoptosis induced by the metals, showing a concentration-dependent pattern to varying extents. These findings strongly support the role of FX in managing toxicities induced by environmental pollutants in bones and in addressing bone diseases associated with molecular bases of oxidative stress, apoptosis, and bioenergetic disruption.

Exploring the impact of 2-hydroxyestradiol on heme oxygenase-1 to combat oxidative stress in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation driven by complex signaling pathways. Recent therapeutic approaches focus on small molecules targeting intracellular signaling to address specific physiological aspects of the disease. Previously we identified a small molecule, 2-hydroxyestradiol (2-OHE2), an inhibitor of TNF-α by an in-silico study. In the present study, our aim was to explore the efficacy of 2-OHE2 by studying the proteome profile of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) using SWATH-MS and validate its therapeutic potential in RA by in-vitro studies. Oxidative stress was assessed using various biochemical assays, and cellular bioenergetics were analyzed with the Seahorse XFe96 Analyzer. We identified 396 differential proteins by SWATH-MS, and 82 showed significant changes. PharmMapper analysis revealed the association of 2-OHE2 with HMOX1 (HO-1), confirmed by SWATH-MS data. Also, we revealed that 2-OHE2 enhanced the expression of HO-1 and lowered oxidative stress via activating the Nrf2/KEAP1/HO-1 pathway. Further, 2-OHE2 has been found to boost cellular respiration and ATP production. Our findings thus suggest that 2-OHE2 possesses therapeutic potential as an antioxidant for RA treatment, effective at low dosages.

Netupitant Exhibits Potent Activity on Mycobacterium tuberculosis Persisters.

In Mycobacterium tuberculosis (Mtb), persisters are genotypically drug-sensitive bacteria that nonetheless survive antibiotic treatment. Persisters represent a significant challenge to shortening TB treatment and preventing relapse, underscoring the need for new therapeutic strategies. In this study, we screened 2,336 FDA-approved compounds to identify agents that enhance the sterilizing activity of standard anti-TB drugs and prevent the regrowth of persisters. Netupitant (NTP), an FDA-approved antiemetic, emerged as a promising candidate with bacteriostatic activity on its own. However, in combination with isoniazid (INH) and rifampicin (RIF), NTP eliminated viable Mtb cells within 7 days, achieving a >6-log reduction in colony-forming units (CFUs) compared to the 2.5-log reduction observed with INH-RIF alone. NTP also demonstrated broad-spectrum efficacy, enhancing the activity of multiple TB drugs, including ethambutol, moxifloxacin, amikacin, and bedaquiline. Notably, NTP retained its potency under hypoxic and caseum-mimicking conditions, both of which are known to enrich for non-replicating, drug-tolerant cells. Interestingly, under hypoxic conditions, NTP demonstrated strong tuberculocidal activity, achieving an approximate 4-log CFU reduction, whereas high-dose INH-RIF was ineffective. Transcriptomic analysis revealed that NTP primarily disrupts cellular bioenergetics, with significant downregulation observed in activities associated with the electron transport chain, oxidative phosphorylation, NADH-ubiquinone oxidoreductase, succinate dehydrogenase, and ATP synthesis. While further studies are required to decipher the mechanism of action and resistance profile of NTP, and to assess its in vivo efficacy, these findings underscore its potential as a promising adjunct to existing TB therapies.

The peritumoral edema index and related mechanisms influence the prognosis of GBM patients.

Peritumoral brain edema (PTBE) represents a characteristic phenotype of intracranial gliomas. However, there is a lack of consensus regarding the prognosis and mechanism of PTBE. In this study, clinical imaging data, along with publicly available imaging data, were utilized to assess the prognosis of PTBE in glioblastoma (GBM) patients, and the associated mechanisms were preliminarily analyzed. We investigated relevant imaging features, including edema, in GBM patients using ITK-SNAP imaging segmentation software. Risk factors affecting progression-free survival (PFS) and overall survival (OS) were assessed using a Cox proportional hazard regression model. In addition, the impact of PTBE on PFS and OS was analyzed in clinical GBM patients using the Kaplan-Meier survival analysis method, and the results further validated by combining data from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). Finally, functional enrichment analysis based on TCIA and TCGA datasets identified several pathways potentially involved in the mechanism of edema formation. This study included a total of 32 clinical GBM patients and 132 GBM patients from public databases. Univariate and multivariate analyses indicated that age and edema index (EI) are independent risk factors for PFS, but not for OS. Kaplan-Meier curves revealed consistent survival analysis results between IE groups among both clinical patients and TCIA and TCGA patients, suggesting a significant effect of PTBE on PFS but not on OS. Furthermore, functional enrichment analysis predicted the involvement of several pathways related mainly to cellular bioenergetics and vasculogenic processes in the mechanism of PTBE formation. While these novel results warrant confirmation in a larger patient cohort, they support good prognostic value for PTBE assessment in GBM. Our results indicate that a low EI positively impacts disease control in GBM patients, but this does not entirely translate into an improvement in OS. Multiple genes, signaling pathways, and biological processes may contribute to the formation of peritumoral edema in GBM through cytotoxic and vascular mechanisms.

Signaling Pathways Concerning Mitochondrial Dysfunction: Implications in Neurodegeneration and Possible Molecular Targets.

Mitochondrion is an important organelle present in our cells responsible for meeting energy requirements. All higher organisms rely on efficient mitochondrial bioenergetic machinery to sustain life. No other respiratory process can produce as much power as generated by mitochondria in the form of ATPs. This review is written in order to get an insight into the magnificent working of mitochondrion and its implications in cellular homeostasis, bioenergetics, redox, calcium signaling, and cell death. However, if this machinery gets faulty, it may lead to several disease states. Mitochondrial dysfunctioning is of growing concern today as it is seen in the pathogenesis of several diseases which includes neurodegenerative disorders, cardiovascular disorders, diabetes mellitus, skeletal muscle defects, liver diseases, and so on. To cover all these aspects is beyond the scope of this article; hence, our study is restricted to neurodegenerative disorders only. Moreover, faulty functioning of this organelle can be one of the causes of early ageing in individuals. This review emphasizes mutations in the mitochondrial DNA, defects in oxidative phosphorylation, generation of ROS, and apoptosis. Researchers have looked into new approaches that might be able to control mitochondrial failure and show a lot of promise as treatments.

A novel m.5906G > a variant in MT-CO1 causes MELAS/Leigh overlap syndrome.

The MELAS/Leigh overlap syndrome manifests with a blend of clinical and radiographic traits from both MELAS and LS. However, the association of MELAS/Leigh overlap syndrome with MT-CO1 gene variants has not been previously reported. In this study, we report a patient diagnosed with MELAS/Leigh overlap syndrome harboring the m.5906G > A variant in MT-CO1, with biochemical evidence supporting the pathogenicity of the variant. The variant m.5906G > A that led to a synonymous variant in the start codon of MT-CO1 was filtered as the candidate disease-causing variant of the patient. Patient-derived fibroblasts were used to generate a series of monoclonal cells carrying different m.5906G > A variant loads for further functional assays. The oxygen consumption rate, ATP production, mitochondrial membrane potential and lactate assay indicated an impairment of cellular bioenergetics due to the m.5906G > A variant. Blue native PAGE analysis revealed that the m.5906G > A variant caused a deficiency in the content of mitochondrial oxidative phosphorylation complexes. Furthermore, molecular biology assays performed for the pathogenesis, mtDNA copy number, mtDNA-encoded subunits, and recovery capacity of mtDNA were all deficient due to the m.5906G > A variant, which might be caused by mtDNA replication deficiency. Overall, our findings demonstrated the pathogenicity of m.5906G > A variant and proposed a potential pathogenic mechanism, thereby expanding the genetic spectrum of MELAS/Leigh overlap syndrome.

Bioenergetic-active photoluminescent bioactive Nanodressing for proangiogenic MRSA infected wound repair and microenviroment monitoring

Multidrug-resistant bacterial infected wound repair and real-time microenvironment monitoring are still critical challenges, due to the infection-induced inflammation and poor angiogenesis capacity, as well as the complicate wound microenvironment. Herein, we report a multifunctional photoluminescent bioactive hydrogel (GMCB) with cell bioenergy-supplying and excellent antioxidant activities for achieving infection inflammation wound repair and microenvironment monitoring. GMCB was constructed through a bioenergy-supplying poly(citrate-borate) nanomicelle, antioxidant myricetin and gelatin matrix. GMCB possesses injectable, adhesive, photoluminescent and biodegradable properties, demonstrating excellent cellular biocompatibility. GMCB also shows a pH-responsive photoluminescent change based on the reversible crosslinking between borate and myricetin, which would have the potential to monitoring the pH values of wounds. GMCB significantly promotes the cell migration, upregulates the expression of angiogenesis-related genes, efficiently clears reactive oxygen species, and inhibits the expression of inflammatory factors. Importantly, GMCB could release citrate to accelerate the cellular bioenergetics by enhancing mitochondrial membrane potential and ATP levels providing energy for multiple biological activities of cells. GMCB accelerates the repair of methicillin-resistant Staphylococcus aureus (MRSA) infected inflammatory wounds by inhibiting early-stage inflammation, promoting neovascularization and collagen deposition. This work provides a feasible strategy to design bioenergy-reinforcing and intelligent dressing for wound repair-monitoring integration.

Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics

Cellular bioenergetics and mitochondrial dynamics are crucial for the secretion of insulin by pancreatic beta cells in response to elevated levels of blood glucose. To elucidate the interactions between energy production and mitochondrial fission/fusion dynamics, we combine live-cell mitochondria imaging with biophysical-based modeling and graph-based network analysis. The aim is to determine the mechanism that regulates mitochondrial morphology and balances metabolic demands in pancreatic beta cells. A minimalistic differential equation-based model for beta cells is constructed that includes glycolysis, oxidative phosphorylation, calcium dynamics, and fission/fusion dynamics, with ATP synthase flux and proton leak flux as main regulators of mitochondrial dynamics. The model shows that mitochondrial fission occurs in response to hyperglycemia, starvation, ATP synthase inhibition, uncoupling, and diabetic conditions, in which the rate of proton leakage exceeds the rate of mitochondrial ATP synthesis. Under these metabolic challenges, the propensities of tip-to-tip fusion events simulated from the microscopy images of the mitochondrial networks are lower than those in the control group and prevent the formation of mitochondrial networks. The study provides a quantitative framework that couples bioenergetic regulation with mitochondrial dynamics, offering insights into how mitochondria adapt to metabolic challenges.

Targeting PAR2-mediated inflammation in osteoarthritis: a comprehensive in vitro evaluation of oleocanthal’s potential as a functional food intervention for chondrocyte protection and anti-inflammatory effects

BackgroundOsteoarthritis (OA) is a prevalent degenerative joint disease characterized by chronic inflammation and progressive cartilage degradation, ultimately leading to joint dysfunction and disability. Oleocanthal (OC), a bioactive phenolic compound derived from extra virgin olive oil, has garnered significant attention due to its potent anti-inflammatory properties, which are comparable to those of non-steroidal anti-inflammatory drugs (NSAIDs). This study pioneers the investigation into the effects of OC on the Protease-Activated Receptor-2 (PAR-2) mediated inflammatory pathway in OA, aiming to validate its efficacy as a functional food-based therapeutic intervention.MethodsTo simulate cartilage tissue in vitro, human bone marrow-derived mesenchymal stem cells (BMSCs) were differentiated into chondrocytes. An inflammatory OA-like environment was induced in these chondrocytes using lipopolysaccharide (LPS) to mimic the pathological conditions of OA. The therapeutic effects of OC were evaluated by treating these inflamed chondrocytes with various concentrations of OC. The study focused on assessing key inflammatory markers, catabolic enzymes, and mitochondrial function to elucidate the protective mechanisms of OC. Mitochondrial function, specifically mitochondrial membrane potential (ΔΨm), was assessed using Rhodamine 123 staining, a fluorescent dye that selectively accumulates in active mitochondria. The integrity of ΔΨm serves as an indicator of mitochondrial and bioenergetic function. Additionally, Western blotting was employed to analyze protein expression levels, while real-time polymerase chain reaction (RT-PCR) was used to quantify gene expression of inflammatory cytokines and catabolic enzymes. Flow cytometry was utilized to measure cell viability and apoptosis, providing a comprehensive evaluation of OC’s therapeutic effects on chondrocytes.ResultsThe results demonstrated that OC significantly downregulated PAR-2 expression in a dose-dependent manner, leading to a substantial reduction in pro-inflammatory cytokines, including TNF-α, IL-1β, and MCP-1. Furthermore, OC attenuated the expression of catabolic markers such as SOX4 and ADAMTS5, which are critically involved in cartilage matrix degradation. Importantly, OC was found to preserve mitochondrial membrane potential (ΔΨm) in chondrocytes subjected to inflammatory stress, as evidenced by Rhodamine 123 staining, indicating a protective effect on cellular bioenergetics. Additionally, OC modulated the Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL)/Receptor Activator of Nuclear Factor Kappa-Β (RANK) pathway, suggesting a broader therapeutic action against the multifactorial pathogenesis of OA.ConclusionsThis study is the first to elucidate the modulatory effects of OC on the PAR-2 mediated inflammatory pathway in OA, revealing its potential as a multifaceted therapeutic agent that not only mitigates inflammation but also protects cartilage integrity. The preservation of mitochondrial function and modulation of the RANKL/RANK pathway further underscores OC’s comprehensive therapeutic potential in counteracting the complex pathogenesis of OA. These findings position OC as a promising candidate for integration into nutritional interventions aimed at managing OA. However, further research is warranted to fully explore OC’s therapeutic potential across different stages of OA and its long-term effects in musculoskeletal disorders.