Mitochondrial Respiratory Capacity Research Articles

Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism.

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents the accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.

The whole-body and skeletal muscle metabolic response to 14 days of highly controlled low energy availability in endurance-trained females.

This study investigated the effects of 14 days low energy availability (LEA) versus optimal energy availability (OEA) in endurance-trained females on substrate utilization, insulin sensitivity, and skeletal muscle mitochondrial oxidative capacity; and the impact of metabolic changes on exercise performance. Twelve endurance-trained females (V̇O2max 55.2 ± 5.1 mL × min-1 × kg-1) completed two 14-day randomized, blinded, cross-over, controlled dietary interventions: (1) OEA (51.9 ± 2.0 kcal × kg fat-free mass (FFM)-1 × day-1) and (2) LEA (22.3 ± 1.5 kcal × kg FFM-1 × day-1), followed by 3 days OEA. Participants maintained their exercise training volume during both interventions (approx. 8 h × week-1 at 79% heart rate max). Skeletal muscle mitochondrial respiratory capacity, glycogen, and maximal activity of CS, HAD, and PFK were unaltered with LEA. 20-min time trial endurance performance was impaired by 7.8% (Δ -16.8 W, 95% CI: -23.3 to -10.4, p < .001) which persisted following 3 days refueling post-LEA (p < .001). Fat utilization was increased post-LEA as evidenced by: (1) 99.4% (p < .001) increase in resting plasma free fatty acids (FFA); (2) 270% (p = .007) larger reduction in FFA in response to acute exercise; and (3) 28.2% (p = .015) increase in resting fat oxidation which persisted during submaximal exercise (p < .001). These responses were reversed with 3 days refueling. Daily glucose control (via CGM), HOMA-IR, HOMA-β, were unaffected by LEA. Skeletal muscle O2 utilization and carbohydrate availability were not limiting factors for aerobic exercise capacity and performance; therefore, whether LEA per se affects aspects of training quality/recovery requires investigation.

Effects of concentric and eccentric exercise regimens on bioenergetic efficiency of lymphocytes in sedentary males.

Eccentric exercise training (EET) increases physical performance while having lower metabolic demand than concentric exercise training (CET). Whether EET influences bioenergetic efficiency in peripheral blood mononuclear cells (PBMCs) remains unclear. This study investigates the effects of EET and CET on PBMC phenotypes and mitochondrial functions in blood. Thirty three sedentary healthy males were randomly assigned to either EET (n=11) or CET (n=11) that performed at progressively increased from 60% to 80% of maximal absolute workload for 30min/day, 5days/week for 6weeks, or a control group (n=11) that did not receive any exercise intervention. A graded exercise stress test (GXT) was performed before and after the intervention. PBMC phenotypes and mitochondrial respiratory capacity were analyzed using flowcytometry and high-resolution respirometry, respectively. In the same absolute workload, EET elicited lower heart rate and rating of perceived exertion than CET. However, EET as CET increased the VO2 level at the ventilatory threshold. Notably, both EET and CET increased central memory (CD45RO+/CD62+/CD3+) T cells and decreased effector memory T cells reexpressing CD45RA (CD45RA+/CD62-/CD3+). Moreover, the two exercise regimens diminished the loss of mitochondrial membrane potential (ΔΨm) caused by GXT, increased maximal/reserve O2 consumption rates (OCR), and bioenergetic health index in intact PBMCs and enhanced complex I-/II-related OCR in PBMCs with a substrate-rich environment. EET improves aerobic fitness with a lower cardiovascular response to exercise than CET. Moreover, EET as CET reduces senescent T-cell distribution in blood and improves PBMC bioenergetic efficiency by stabilizing ΔΨm and increasing capacity of oxidative phosphorylation.

Adalimumab Treatment Effects on Inflammation and Adipose Tissue Mitochondrial Respiration in Hidradenitis Suppurativa.

Tumour necrosis factor (TNF)-α is a proinflammatory marker and has been shown to affect mitochondrial function in different tissues. We investigated the effect on adipose tissue (AT) inflammation and mitochondrial respiration in patients with hidradenitis suppurativa (HS) after 12 weeks of treatment with adalimumab, a TNF-α inhibitor. We sampled blood and an AT biopsy from 13 patients with HS and 10 control subjects after an overnight fast. The patients were retested after at least 12 weeks of treatment with adalimumab (40 mg/week). We measured macrophage content and mitochondrial respiration in the AT and interleukin (IL)-1β, IL-6, IL-10, high-sensitivity C-reactive protein (hsCRP), interferon-γ, TNF-α, adiponectin and leptin in plasma. Clinical scores and Dermatology Quality of Life Index (DLQI) were assessed. We found a higher anti-inflammatory macrophage content (CD206+) in the patient group compared with the control group, but no differences between before and after the intervention. No difference in mitochondrial respiration was observed. We observed higher plasma IL-6 and hsCRP concentrations in patients with HS compared to controls, with no differences before and after the intervention. The difference between controls and HS patients was abolished after the intervention. HS patients improved their DLQI after the intervention with no change in clinical scores. Treatment with adalimumab in patients with HS does not alter AT inflammation or mitochondrial respiratory capacity; however, we did see a higher content of anti-inflammatory macrophages in the patient group compared with the control group.

Atrial pacing improves mitochondrial function in peripheral blood mononuclear cells in patients with cardiac implantable electronic devices.

Mitochondrial dysfunction contributes significantly to the development of atrial fibrillation (AF). Conflicting data regarding the atrial pacing and the risk of AF existed, and the impact of atrial pacing on mitochondrial function remains unknown. Therefore, we sought to examine the association between atrial pacing percentage and mitochondrial function in patients with cardiovascular implantable electronic devices (CIEDs) with atrial pacing capability. This is a cross-sectional study involving 183 patients with CIEDs with atrial pacing capability. The oxidative stress and mitochondrial function were determined in peripheral blood mononuclear cells (PBMCs). Among 183 patients, 55.7% had permanent pacemakers, 7.7% had defibrillators, and 36.6% had cardiac resynchronization therapy. Mean age was 67.5 ± 14.7 yr with 51% being male. Mean left ventricular ejection fraction (LVEF) was 53.9 ± 16.8%. We demonstrated that the presence of atrial pacing above 50% correlated with higher levels of mitochondrial spared respiratory capacity (P = 0.043) and coupling efficiency (P = 0.045). After adjusting with multiple linear regression for age, sex, LVEF, history of AF, sick sinus syndrome, comorbidities, estimated glomerular filtration rate (eGFR), cardiac resynchronization therapy (CRT), and percentage of ventricular pacing, our findings revealed a statistically significant association between a higher percentage of atrial pacing and increased spared respiratory capacity (β, 0.217, P = 0.046), lower nonmitochondrial respiration (β, -0.230; P = 0.023), and proton leak (β, -0.247; P = 0.022). We demonstrated that atrial pacing enhances mitochondrial performance in PBMCs and left ventricular contractile performance in patients with CIEDs. This observation may serve as an additional support for the preventive effect of atrial pacing in the prevention of atrial arrhythmia.NEW & NOTEWORTHY Atrial pacing enhances mitochondrial spare respiratory capacity and reduces proton leak. This finding may provide further evidence supporting the preventive role of atrial pacing in reducing the risk of atrial fibrillation in patients with cardiac implantable electronic devices.

Regulatory roles of histamine receptor in astrocytic glutamate clearance under conditions of increased glucose variability

In diabetic patients, repeated episodes of hypoglycemia can increase glucose variability (GV), which may lead to glutamate neurotoxicity in the brain and consequently affect cognitive functions. Astrocytes play a crucial role in regulating the balance of glutamate within the brain, and their function is influenced by the histamine receptor (HR) signaling pathway. However, the specific role of this mechanism under conditions of high GV is not yet clear. The results showed that increased GV resulted in decreased expression of HRs in mice hippocampus and astrocytes cultured in vitro. Additionally, a decrease in the expression of proteins related to glutamate metabolic clearance was observed, accompanied by a reduction in glutamate reuptake capacity. Notably, the intervention with histidine/histamine was able to reverse the above changes. Further mechanistic studies showed that inhibition of HRs that increased GV led to significant disturbances in astrocytic mitochondrial function. These abnormalities encompassed increased fragmentation morphology and the accumulation of reactive oxygen species, accompanied by decreased mitochondrial respiratory capacity and dysregulation of dynamics. Distinct HR subtypes exhibited variations in the modulation of mitochondrial function, with H3R demonstrating the most pronounced impact. The overexpression of H3R could enhance glutamate metabolic by reversing disturbances in mitochondrial dynamics. Therefore, this study suggests that H3R is able to maintain glutamate metabolic clearance capacity and exert neuroprotective effects in astrocytes that increased GV by regulating mitochondrial dynamic balance. This provides an important basis for potential therapeutic targets for diabetes-related cognitive dysfunction.

Validation of metaxin-2 deficient C. elegans as a model for MandibuloAcral Dysplasia associated to mtx-2 (MADaM) syndrome

MandibuloAcral Dysplasia associated to MTX2 gene (MADaM) is a recently described progeroid syndrome (accelerated aging disease) whose clinical manifestations include skin abnormalities, growth retardation, and cardiovascular diseases. We previously proposed that mtx-2-deficient C. elegans could be used as a model for MADaM and to support this, we present here our comprehensive phenotypic characterization of these worms using atomic force microscopy (AFM), transcriptomic, and oxygen consumption rate analyses. AFM analysis showed that young mtx-2-less worms had a significantly rougher, less elastic cuticle which becomes significantly rougher and less elastic as they age, and abnormal mitochondrial morphology. mtx-2 C. elegans displayed slightly delayed development, decreased pharyngeal pumping, significantly reduced mitochondrial respiratory capacities, and transcriptomic analysis identified perturbations in the aging, TOR, and WNT-signaling pathways. The phenotypic characteristics of mtx-2 worms shown here are analogous to many of the human clinical presentations of MADaM and we believe this validates their use as a model which will allow us to uncover the molecular details of the disease and develop new therapeutics and treatments.

Transgelin 2 guards T cell lipid metabolism and antitumour function.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss

Sarcopenia, which refers to age-related muscle loss, presents a significant challenge for the aging population. Age-related changes that contribute to sarcopenia include cellular senescence, decreased muscle stem cell number and regenerative capacity, impaired autophagy, and mitochondrial dysfunction. Metformin, an anti-diabetic agent, activates AMP-activated protein kinase (AMPK) and affects various cellular processes in addition to reducing hepatic gluconeogenesis, lowering blood glucose levels, and improving insulin resistance. However, its effect on skeletal muscle cells remains unclear. This study aimed to investigate the effects of metformin on age-related muscle loss using a late passage C2C12 cell model. The results demonstrated that metformin alleviated hallmarks of cellular senescence, including SA-β-gal activity and p21 overexpression. Moreover, treatment with pharmacological concentrations of metformin restored the reduced differentiation capacity in late passage cells, evident through increased myotube formation ability and enhanced expression of myogenic differentiation markers such as MyoD, MyoG, and MHC. These effects of metformin were attributed to enhanced autophagic activity, normalization of mitochondrial membrane potential, and improved mitochondrial respiratory capacity. These results suggest that pharmacological concentrations of metformin alleviate the hallmarks of cellular senescence, restore differentiation capacity, and improve autophagic flux and mitochondrial function. These findings support the potential use of metformin for the treatment of sarcopenia.

Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells.

Lipid enals are electrophilic products of lipid peroxidation that induce genotoxic and proteotoxic stress by covalent modification of DNA and proteins, respectively. As lipid enals accumulate to substantial amounts in visceral adipose during obesity and aging, we hypothesized that biogenic lipid enals may represent an endogenously generated, and therefore physiologically relevant, senescence inducers. To that end, we identified that 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE) or 4-oxo-2-nonenal (4-ONE) initiate the cellular senescence program of IMR90 fibroblasts and murine adipose stem cells. In such cells, lipid enals induced accumulation of γH2AX foci, increased p53 signaling, enhanced expression of p21Cip1, and upregulated the expression and secretion of numerous cytokines, chemokines, and regulatory factors independently from NF-κB activation. Concomitantly, lipid enal treatment resulted in covalent modification of mitochondrial proteins, reduced mitochondrial spare respiratory capacity, altered nucleotide pools, and increased the phosphorylation of AMP kinase. Lipid-induced senescent cells upregulated BCL2L1 (Bcl-xL) and BCL2L2 (Bcl-w). and were resistant to apoptosis while pharmacologic inhibition of BAX/BAK macropores attenuated lipid-induced senescence. Insitu, the 4-HNE scavenger L-carnosine ameliorated the development of the cellular senescence, while in visceral fat of obese C57BL/6J mice, L-carnosine reduced the abundance of 4-HNE-modified proteins and blunted the expression of senescence biomarkers CDKN1A (p21Cip1), PLAUR, BCL2L1, and BCL2L2. Taken together, the results suggest that lipid enals are endogenous regulators of cellular senescence and that biogenic lipid-induced senescence (BLIS) may represent a mechanistic link between oxidative stress and age-dependent pathologies.

DACRA induces profound weight loss, satiety control, and increased mitochondrial respiratory capacity in adipose tissue.

Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue. Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336. A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and β-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT. These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss.

Luteolin alleviates muscle atrophy, mitochondrial dysfunction and abnormal FNDC5 expression in high fat diet-induced obese rats and palmitic acid-treated C2C12 myotubes

Obesity is associated with a series of skeletal muscle impairments and dysfunctions, which are characterized by metabolic disturbances and muscle atrophy. Luteolin is a phenolic phytochemical with broad pharmacological activities. The present study aimed to evaluate the protective effects of Luteolin on muscle function and explore the potential mechanisms in high-fat diet (HFD)-induced obese rats and palmitic acid (PA)-treated C2C12 myotubes. Male Sprague-Dawley (SD) rats were fed with a control diet or HFD and orally administrated 0.5% sodium carboxymethyl cellulose (vehicle) or Luteolin (25, 50 and 100 mg/kg, respectively) for 12 weeks. The results showed that Luteolin ameliorated HFD-induced body weight gain, glucose intolerance and hyperlipidemia. Luteolin also alleviated muscle atrophy, decreased ectopic lipid deposition and prompted muscle-fiber-type conversion in the skeletal muscle. Meanwhile, we observed an evident improvement in mitochondrial quality control and respiratory capacity, accompanied by reduced oxidative stress. Mechanistic studies indicated that AMPK/SIRT1/PGC-1α signaling pathway plays a key role in the protective effects of Luteolin on skeletal muscle in the obese states, which was further verified by using specific inhibitors of AMPK and SIRT1. Moreover, the mRNA expression levels of markers in brown adipocyte formation were significantly up-regulated post Luteolin supplementation in different adipose depots. Taken together, these results revealed that Luteolin supplementation might be a promising strategy to prevent obesity-induced loss of mass and biological dysfunctions of skeletal muscle.

Metabolic rate and mitochondrial physiology adjustments in Arctic char (Salvelinus alpinus) during cyclic hypoxia.

Diel fluctuations of oxygen levels characterize cyclic hypoxia and poses a significant challenge to wild fish populations. Although recent research has been conducted on the effects of hypoxia and reoxygenation, mechanisms by which fish acclimatize to cyclic hypoxia remain unclear, especially in hypoxia-sensitive species. We hypothesized that acclimation to cyclic hypoxia requires a downregulation of their aerobic metabolic rate (MR) and an upregulation of mitochondrial respiratory capacities to mitigate constraints on aerobic metabolism and the elevated risk of oxidative stress upon reoxygenation. We exposed Arctic char (Salvelinus alpinus) to ten days of cyclic hypoxia and measured their MR and mitochondrial physiology to determine how they cope with fluctuating oxygen concentrations. We measured oxygen consumption as a proxy of MR and observed that Arctic char defend their standard metabolic rate but decrease their routine metabolic rate during hypoxic phases, presumably through the repression of spontaneous swimming activities. At the mitochondrial level, acute cyclic hypoxia increases oxygen consumption without ADP (CI-LEAK) in liver and heart. Respiration in the presence of ADP (OXPHOS) temporarily increases in the liver and decreases in the heart. Cytochrome c oxidase (COX) affinity with oxygen also increases at day 3 in the liver. However, no change occurs in the brain, which is likely primarily preserved through preferential perfusion (albeit not measured in this study). Finally, in vivo measurements of reactive oxygen species revealed the absence of an oxidative burst in mitochondria in the cyclic hypoxia group. Our study shows that Arctic char acclimatize to cyclic hypoxia through organ-specific mitochondrial adjustments.

6-Gingerol improves lipid metabolism disorders in skeletal muscle by regulating AdipoR1/AMPK signaling pathway

BackgroundTo delve into the precise mechanisms by which 6-gingerol ameliorates lipid metabolism disorders in skeletal muscle. MethodsThe level of triglycerides (TG) was used to evaluate lipid deposition. In skeletal muscle, transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. Additionally, PCR was applied to detect mitochondrial biogenesis, and levels of malondialdehyde (MDA), catalase (CAT), glutathione, r-glutamyl cysteingl+glycine (GSH) and nicotinamide adenine dinucleotide (NADH) were measured to assess mitochondrial oxidative stress levels. In vivo, flow cytometry and immunofluorescence assays were conducted to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Furthermore, the Seahorse XF assays was utilized to assess mitochondrial respiratory capacity. Fluorescence confocal microscopy and molecular docking were applied to analyze the binding of 6-gingerol and adiponectin receptor 1 (AdipoR1). The expression of AdipoR1, AMPK, PGC-1α and SIRT1 were detected by Western Blot. ResultsIn vivo, 6-gingerol could reduce body weight in mice induced by a high-fat diet, enhance metabolic profiles in plasma, decrease lipid accumulation in skeletal muscle and liver, and elevate adiponectin levels. In skeletal muscle, it could restore mitochondrial morphology, boost mitochondrial copy number and biogenesis, and mitigate oxidative stress. In vitro, 6-gingerol may directly interact with AdipoR1 to upregulate the expression of downstream proteins p-AMPK, SIRT1, and PGC-1α, leading to a reduction in lipid deposition, a decrease in ROS production, an increase in mitochondrial membrane potential, and an enhancement of mitochondrial respiratory capacity in C2C12 myotubes. Conclusion6-Gingerol ameliorated lipid metabolism in skeletal muscle by regulating the AdipoR1/AMPK signaling pathway.

Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.

Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.

Atomic vacancies of molybdenum disulfide nanoparticles stimulate mitochondrial biogenesis

Diminished mitochondrial function underlies many rare inborn errors of energy metabolism and contributes to more common age-associated metabolic and neurodegenerative disorders. Thus, boosting mitochondrial biogenesis has been proposed as a potential therapeutic approach for these diseases; however, currently we have a limited arsenal of compounds that can stimulate mitochondrial function. In this study, we designed molybdenum disulfide (MoS2) nanoflowers with predefined atomic vacancies that are fabricated by self-assembly of individual two-dimensional MoS2 nanosheets. Treatment of mammalian cells with MoS2 nanoflowers increased mitochondrial biogenesis by induction of PGC-1α and TFAM, which resulted in increased mitochondrial DNA copy number, enhanced expression of nuclear and mitochondrial-DNA encoded genes, and increased levels of mitochondrial respiratory chain proteins. Consistent with increased mitochondrial biogenesis, treatment with MoS2 nanoflowers enhanced mitochondrial respiratory capacity and adenosine triphosphate production in multiple mammalian cell types. Taken together, this study reveals that predefined atomic vacancies in MoS2 nanoflowers stimulate mitochondrial function by upregulating the expression of genes required for mitochondrial biogenesis.

Silk-based nanocomposite hydrogel balances immune homeostasis via targeting mitochondria for diabetic wound healing

Patients with diabetes frequently experience impaired wound healing, a challenge commonly attributed to immune imbalance and oxidative stress; notably, these issues arise from mitochondrial dysfunction. In this study, we fabricate a naturally derived bioactive hydrogel by incorporating resveratrol-loaded mesoporous polydopamine nanoparticles into silk microfibers-reinforced methacrylated silk network (SS/MPDA@RES), which exhibits appropriate injectability, light-curable performance and mechanical strength. It effectively scavenges excessive ROS to protect mitochondria, restore ATP production and remodel redox homeostasis. More importantly, it promotes mitochondrial biogenesis, respiratory capacity and oxidative phosphorylation via the AMPK/SIRT1/PGC-1α signaling axis, thereby reprogramming macrophages to the anti-inflammatory phenotype. In vivo, SS/MPDA@RES hydrogel promotes wound healing in diabetic rats by modulating immunity, inhibiting early inflammation, and accelerating angiogenesis and collagen deposition. Targeting mitochondria to regulate immune and redox homeostasis provides a novel avenue for the design of future tissue regeneration materials, with SS/MPDA@RES emerging as a potential treatment strategy for diabetic wounds.

Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer's disease astrocytes.

Abnormalities in cellular metabolism are seen early in Alzheimer's disease (AD). Astrocyte support for neuronal function has a high metabolic demand, and astrocyte glucose metabolism plays a key role in encoding memory. This indicates that astrocyte metabolic dysfunction might be an early event in the development of AD. In this paper we interrogate glycolytic and mitochondrial functional changes and mitochondrial structural alterations in patients' astrocytes derived with a highly efficient direct conversion protocol. In astrocytes derived from patients with sporadic (sAD) and familial AD (fAD) we identified reductions in extracellular lactate, total cellular ATP and an increase in mitochondrial reactive oxygen species. sAD and fAD astrocytes displayed significant reductions in mitochondrial spare respiratory capacity, have altered mitochondrial membrane potential and a stressed mitochondrial network. A reduction in glycolytic reserve and glycolytic capacity is seen. Interestingly, glycolytic reserve, mitochondrial spare respiratory capacity and extracellular lactate levels correlated positively with neuropsychological tests of episodic memory affected early in AD. We identified a deficit in the glycolytic enzyme hexokinase 1 (HK1), and correcting this deficit improved the metabolic phenotype in sAD not fAD astrocytes. Importantly, the amount of HK1 at the mitochondria was shown to be reduced in sAD astrocytes, and not in fAD astrocytes. Overexpression of HK1 in sAD astrocytes increases mitochondrial HK1 levels. In fAD astrocytes HK1 levels were unaltered at the mitochondria after overexpression. This study highlights a clear metabolic deficit in AD patient-derived astrocytes and indicates how HK1, with its roles in both oxidative phosphorylation and glycolysis, contributes to this.

Intercellular nanotube-mediated mitochondrial transfer enhances Tcell metabolic fitness and antitumor efficacy.

Mitochondrial loss and dysfunction drive Tcell exhaustion, representing major barriers to successful Tcell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to Tcells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with Tcells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ Tcells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ Tcells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged Tcells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with Tcells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ Tcells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.

Translational Cardiology: Practical Insights into the Coenzyme Q10 Role as Potential Therapeutic Agent for Cardiovascular Disease Treatment via Systematic Review and Meta-Analysis of Prospective Cohort Studies

Background and Objectives: As clinicians seek novel treatment strategies for CVDs, personalized nutrient recommendations are becoming essential. CoQ10, a key component of the mitochondrial electron transport chain, shows promise with proven cardioprotective effects. This systematic review and meta-analysis evaluates the efficacy of CoQ10 supplementation in improving mitochondrial function, systolic performance, and other parameters in CVD. Methods: Analysis included data from PubMed, Embase, and the Cochrane Library up to January 2024. It focused on randomized controlled trials (RCTs) involving adults with cardiovascular diseases (CVDs), comparing CoQ10 with placebo or standard care. Data extraction and quality assessment followed PRISMA guidelines, the Cochrane Collaboration's RoB2 tool, AMSTAR 2, and GRADE. The primary outcome was mitochondrial function (ATP production, respiratory capacity), and the secondary outcome was systolic function (ejection fraction). Findings: CoQ10 supplementation improved ejection fraction (mean difference: 5.6%, 95% CI: 3.2% to 8.0%, p&lt;0.001, I²=25%). The I² statistic for ejection fraction was 25%, indicating low heterogeneity. Mitochondrial function showed increased ATP production (SMD: 0.82, 95% CI: 0.60 to 1.04, p&lt;0.001, I²=30%) and enhanced respiratory capacity (SMD: 0.75, 95% CI: 0.53 to 0.97, p&lt;0.001, I²=28%). The I² statistics for ATP production and mitochondrial respiratory capacity were 30% and 28%, respectively, suggesting low to moderate heterogeneity. Sensitivity analyses confirmed the robustness of the results, with consistent effect sizes and confidence intervals across both fixed-effect and random-effects models, and no significant changes upon excluding high-risk studies. Publication bias was low, as indicated by funnel plots and Egger's test (p=0.12). Limitations: Larger-scale RCTs are needed to confirm findings and determine the optimal dosage and duration of CoQ10 therapy. Conclusion: CoQ10 has been consistently shown to improve mitochondrial function, systolic performance, and other key cardiovascular health parameters in CVD patients. The evidence here presented strongly bridges the gaps between the current research and clinical applications and supports clinicians in implementing the prescription of CoQ10 supplementation as an intervention evidence-based therapeutic agent that effectively improves cardiovascular health outcomes