Search Results (596)

Familial partial lipodystrophy type 3 (FPLD3) is a rare autosomal dominant disorder caused by mutations in peroxisome proliferator-activated receptor gamma(PPARG), which encodes the key adipogenic transcription factor peroxisome proliferator-activated receptor gamma(PPARγ). Clinical diagnosis is challenging due to phenotypic overlap with common metabolic syndromes. We identified a novel PPARG variant in a Chinese family and performed comprehensive functional characterization to elucidate its pathogenic mechanism. The proband, a 15-year-old boy presenting with atypical fat distribution, severe insulin resistance, hypertriglyceridemia, and pancreatitis, underwent clinical evaluation and whole-exome sequencing. The identified variant was confirmed by Sanger sequencing. Its functional impact was assessed through in silico modeling, luciferase reporter assays, protein stability analysis (cycloheximide chase), and evaluation of mitochondrial function (JC-1 staining) and adipocyte gene expression in cellular models. A heterozygous PPARG c.634C>T (p.Arg212Trp, R212W) variant was identified and segregated with the phenotype. Functional studies revealed that the R212W mutant exhibits a partial loss of transcriptional activity (~40% of wild-type) while retaining ligand sensitivity. Crucially, we demonstrated that the mutant protein has significantly reduced stability due to accelerated degradation. In adipocyte models, R212W expression led to impaired mitochondrial membrane potential, depleted cellular ATP levels, and downregulated expression of key metabolic genes (glucose transporter 4[GLUT4], adiponectin[ADIPOQ], fatty acid binding protein 4[FABP4], lipoprotein lipase[LPL], perilipin 1[PLIN1]). These functional deficits were partially rescued by treatment with the PPARγ agonist rosiglitazone. We report a novel pathogenic PPARG R212W variant associated with FPLD3. Our data extend beyond a simple loss-of-function model by establishing a multi-faceted pathogenic mechanism involving protein destabilization, mitochondrial dysfunction, and cellular bioenergetic failure. The partial rescue by rosiglitazone suggests a potential therapeutic avenue. This study underscores the importance of integrating clinical phenotyping with deep functional analysis to diagnose and understand rare monogenic lipodystrophies. Full article

Vascular inflammation and endothelial dysfunction are key drivers in the development of cardiovascular and neurovascular diseases. Mitochondrial dysfunction and oxidative stress further amplify inflammatory cascades, emphasising the need for targeted strategies that restore endothelial homeostasis at the subcellular level. Hydrogen sulphide (H₂S) donors, such as AP39, offer cytoprotective benefits but are limited by short half-life and rapid release of the active compound, H₂S. We developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating AP39 (PLGA-AP39) to achieve sustained, mitochondria-targeted H₂S delivery. Nanoparticles were characterised by size, polydispersity, zeta potential, encapsulation efficiency, and in vitro release kinetics. Human umbilical vein endothelial cells (HUVEC) were exposed to TNF-α to induce inflammation, followed by treatment with free AP39 or PLGA-AP39. Anti-inflammatory effects were assessed by measuring IL-6, IL-8, and TGF-β levels. Mitochondrial function was evaluated using a Seahorse XFe24 Analyser, membrane potential assays, and mitochondrial ROS detection. Moreover, we investigated vascular function by analysing capillary-like tube formation and wound closure in response to treatments. PLGA-AP39 nanoparticles displayed a uniform size (~227 nm), low PDI, and high encapsulation efficiency (>78%). Sustained AP39 release was observed over seven days. Treatment with PLGA-AP39 significantly restored TNF-α-induced endothelial dysfunction and reduced TNF-α-induced release of IL-6, IL-8, and TGF-β compared to untreated controls. Seahorse analysis revealed restoration of maximal respiration and increased spare respiratory capacity. Encapsulated AP39 also preserved mitochondrial membrane potential and reduced mitochondrial ROS production, demonstrating enhanced protection against inflammation-induced metabolic dysfunction. This work establishes a novel nanoparticle-based strategy for prolonged, mitochondria-specific H₂S delivery to counteract vascular inflammation and enhance endothelial bioenergetics. The results from this work are pioneering in the generation of a novel delivery method for H₂S donors employing PLGA and represent a promising therapeutic avenue for treating chronic vascular inflammatory disorders. Full article

Coenzyme Q₁₀ (CoQ₁₀) is an essential lipid-soluble molecule that plays a central role in mitochondrial energy production as a mobile electron carrier. In addition to its bioenergetic function, CoQ₁₀ participates in antioxidant defense, redox homeostasis, lipid and nucleotide metabolism, and mitochondrial quality control. Primary CoQ₁₀ deficiencies are rare inherited mitochondrial disorders caused by pathogenic variants in nuclear genes involved in CoQ₁₀ biosynthesis. These defects lead to reduced CoQ₁₀ levels and impaired mitochondrial functions. Clinically, primary CoQ₁₀ deficiencies display remarkable phenotypic heterogeneity, ranging from isolated organ involvement, notably renal or cerebellar disease, to severe multisystemic disorders affecting the nervous system, skeletal muscle, heart, and other organs. Disease onset spans from the antenatal period to adulthood, and clinical severity varies widely, even among patients carrying variants in the same gene. This diversity cannot be fully explained by defective ATP production alone. Growing evidence indicates that disruption of non-bioenergetic functions of CoQ₁₀, including oxidative stress regulation and CoQ-dependent metabolic pathways, contributes significantly to disease pathophysiology and tissue vulnerability. In this review, we summarize current knowledge on CoQ₁₀ biology, biosynthesis, and the clinical spectrum of primary CoQ₁₀ deficiencies, and we discuss emerging mechanisms linking CoQ₁₀ depletion to mitochondrial dysfunctions and human diseases. Full article

Identifying a metabolic rescue for mitochondrial toxins induced neurodegeneration is a promising therapeutic target. Dopaminergic neurons are high energy dependent neurons, owing to their metabolic functions, and this makes them vulnerable in conditions of bioenergetic failure and mitochondrial dysfunction. In this study, we explored the protective potential of sodium propionate, a short-chain fatty acid and metabolic precursor of succinate, against mitochondrial toxin-induced neurotoxicity in MN9D dopaminergic cells. Cells were treated with 200 µM sodium propionate after exposure to 1.5 µM rotenone or 10 µM antimycin A, and cell viability, intracellular ATP levels, reactive oxygen species (ROS) generation, and dopaminergic markers were assessed. Our results show that sodium propionate significantly attenuates mitochondrial toxin-induced loss of cell viability and ATP depletion while reducing oxidative stress and preserving the expression of enzymes involved in catecholamine biosynthesis pathway, including tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH). These findings suggest that sodium propionate confers functional protection to dopaminergic neurons under mitochondrial toxin stress. Sodium propionate is proposed to act as a metabolic precursor to succinyl-CoA, thereby replenishing tricarboxylic acid cycle intermediates and supporting cellular metabolic homeostasis. Under Complex I inhibition (rotenone) and complex III inhibition (antimycin A), sodium propionate treatment was associated with preservation of cellular ATP levels. Across conditions, sodium propionate treatment was associated with improved cell viability, reduced oxidative stress associated signals, and preservation of dopaminergic function. Together, these data indicate that sodium propionate supports dopaminergic neuronal resilience through toxin-dependent metabolic and cellular stress modulating effects. Full article

The mitochondrial outer membrane (OMM) plays a crucial role in maintaining cellular homeostasis by regulating mitochondrial dynamics, organelle interactions, and stress responses. In peripheral neurons—cells with high metabolic demands and long axons—the OMM acts as a vital platform for coordinating bioenergetics, calcium signaling, and redox balance. Ganglioside-induced differentiation-associated protein 1 (GDAP1), an OMM-anchored protein, has emerged as a key regulator of mitochondrial fission and transport, redox homeostasis, and mitochondrial membrane contact sites (MCSs). Genetic variants in GDAP1 cause Charcot–Marie–Tooth disease (CMT), emphasizing its essential role in peripheral nerve function. This review highlights the multifaceted functions of GDAP1 in neuronal physiology and as a model protein that integrates organelle communication and mitochondrial biology. We further discuss how GDAP1 dysfunction leads to structural and functional impairments in peripheral neurons, proposing the OMM and its microenvironment as critical targets for therapeutic intervention in inherited neuropathies. Full article

Background: Mitochondrial dysfunction is a fundamental driver of skin aging, making the enhancement of cellular bioenergetics an important strategy in dermocosmetic innovation. Cornus officinalis fruit extract (COFE), standardized for iridoid glycosides, was investigated for its ability to modulate mitochondrial function and counteract photo-oxidative stress associated with skin aging. Methods: Human dermal fibroblasts were treated with COFE to evaluate mitochondrial bioactivation. Transcriptomic changes were assessed using RNA sequencing (RNA-seq), with key mitochondrial genes validated by qPCR. AMPK phosphorylation, intracellular ATP content, NAD⁺/NADH ratio, and mitochondrial membrane potential (ΔΨm) were quantified as functional indicators of mitochondrial performance. To examine anti-aging relevance, a reconstructed human epidermis model was challenged with UVA and retinol to induce photo-oxidative stress. COFE’s effects on inflammatory (IL-1α), hydration (AQP3), proliferation (Ki67), and barrier-related (PKCα) markers were subsequently analyzed. Results: COFE was associated with activation of AMPK signaling and coordinated upregulation of OXPHOS-related genes in dermal fibroblasts, increasing ATP by 30.00%, the NAD⁺/NADH ratio by 158.71%, and ΔΨm by 158.82%. It also reduced IL-1α and upregulated AQP3, Ki67, and PKCα in a UVA/retinol-challenged epidermis model. In vivo, a 1% COFE eye cream produced statistically significant improvements across hydration, barrier function, redness, skin tone, wrinkles, elasticity, and periorbital contour after 28 days. Conclusions: COFE functions as an AMPK-associated mitochondrial bioenergetic modulator that enhances cellular energy metabolism and mitigates photo-oxidative stress in skin-relevant experimental models. The concordance between mechanistic findings and clinical outcomes supports COFE as a promising anti-aging active ingredient for dermocosmetic applications. Full article

Background: Human exposure to endocrine-disrupting chemicals (EDCs) is increasingly linked to male reproductive dysfunction, but underlying mechanisms remain unclear. This study aimed to evaluate how selected pharmacological (dihydroxyflutamide, 2OH-FTA; bicalutamide, BIC) and agrochemical (lindane, βHCH; permethrin, PERM; mancozeb, MNZ; tributyltin oxide, TBTO) EDCs affect mitochondrial function in human spermatozoa with parameters within World Health Organization (WHO) reference ranges. Methods: Human sperm cells were exposed ex vivo to 0.1–1000 nM of each compound. Mitochondrial respiration was measured using polarography, assessing oxygen consumption in active (V₃) and resting (V₄) states, and the respiratory control ratio (RCR) was calculated as an index of mitochondrial coupling. Results: Both 2OH-FTA and BIC reduced RCR in a concentration-dependent manner, mainly due to increases in V₄, with BIC showing the strongest effect. βHCH produced a similar pattern, elevating V₄ and decreasing RCR. In contrast, PERM, MNZ, and TBTO caused near-complete collapse of both V₃ and V₄ even at sub-nanomolar concentrations, indicating severe, concentration-independent mitochondrial toxicity. Conclusions: Sperm mitochondria are highly sensitive to EDCs, and distinct compounds exert different bioenergetic effects. Mitochondrial respiration assays provide a useful tool for ex vivo toxicological screening and risk assessment. Full article

Background/Objectives: Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder. Current AD therapies offer minimal benefits and do not prevent or repair neuronal damage. More effective therapeutic approaches are needed to restore normal bioenergetics and metabolic function to AD neurons. Simufilam is a small-molecule oral drug that targets filamin A, a scaffolding protein in brain cells. Phase III clinical trials of simufilam failed to show any significant cognitive or functional improvements in AD patients. The purpose of this study is to identify and explain the molecular mechanisms that may have contributed to this drug’s lack of clinical success. Methods: Our study investigates the effects of simufilam on amyloid processing, neuronal health, and mitochondrial functioning in the SH-SY5Y human neuronal cell model. SH-SY5Y cells were differentiated into neurons using 10 µM retinoic acid. Undifferentiated and differentiated SH-SY5Y were exposed to simufilam (5 µM, 50 µM; 24 hr). Results: Simufilam did not affect the expression of genes involved in amyloid processing. Amyloid precursor protein (APP), β-secretase, and α-secretase mRNA levels in simufilam-treated SH-SY5Y cells were all unchanged compared to untreated cells. However, amyloidogenic β-secretase protein was significantly increased (fold change 1.17) at 50 µM of simufilam only in differentiated SH-SY5Y cells without affecting APP or α-secretase protein expression. Simufilam at the 50 µM concentration reduced brain-derived neurotrophic factor protein levels (fold change 0.7) only in differentiated SH-SY5Y. Further, simufilam did not improve mitochondrial genes or structure. Conclusions: Our results align with clinical outcomes and indicate that insufficient activity across multiple tests of ability to impact processes related to neuronal health can serve as a preliminary indicator of limited clinical utility. Full article

Nicotine vaping has surged in recent years, particularly among young adults, and is strongly linked with concurrent alcohol use. Separately, chronic excessive alcohol use drives hypertension and cardiomyopathy, while nicotine vaping is linked to a modest rise in cardiovascular disease incidence and mortality. However, little is known about how concurrent use interacts to affect protein expression in the cardiovascular system. The aim of this study was to determine differential cardiac protein expression in mice exposed to concurrent chronic-plus-binge alcohol and nicotine vaping use. Male C57BL6/J mice received a 20-day 5% ethanol diet with 5 g/kg ethanol binges on days 10 and 20, alongside isocaloric controls. During this period, they were also exposed nightly to either 5% nicotine salt vapor, vegetable glycerin/propylene glycol vehicle vapor, or room air. The left ventricular free wall was collected and analyzed using discovery-based proteomics and subsequent Ingenuity Pathway Analysis. A total of 3144 proteins were identified across all groups. Compared to air-exposed, control-fed mice, 201 proteins were significantly altered by ethanol, 101 proteins by nicotine vaping, and 159 proteins by combined exposure. Both ethanol and nicotine vaping influenced pathways involved in lipid homeostasis, extracellular matrix remodeling, and mitochondrial bioenergetics; however, these alterations did not uniformly manifest in the dual-use group. This pattern highlights the nonadditive and potentially interaction-dependent nature of alcohol and nicotine vaping effects on cardiovascular protein expression patterns that may contribute to a distinct functional phenotype. Full article

Glutamine metabolism has emerged as one of the most critical bioenergetic and biosynthetic programs sustaining leukemic cell growth, survival, stemness and therapeutic resistance. In both acute and chronic leukemias, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), malignant cells display a strong dependency on extracellular glutamine to support mitochondrial respiration, anabolic biosynthesis and redox homeostasis. This dependency is reinforced by oncogenic signaling networks, post-transcriptional metabolic regulation and microenvironmental adaptation within the bone marrow niche. Therapeutic strategies targeting glutamine utilization, including glutaminase inhibition, transporter blockade and enzymatic glutamine depletion, have demonstrated robust antileukemic activity in preclinical models, and early clinical efforts have begun to explore glutamine-directed interventions in myeloid neoplasms. However, metabolic plasticity, microenvironment-derived nutrient buffering and systemic toxicity remain significant limitations to clinical translation. This review provides a detailed synthesis of the biochemical framework of glutamine metabolism in leukemia, the molecular mechanisms enforcing glutamine addiction, the downstream functional consequences on proliferation, redox balance and leukemic stem cell biology, the current landscape of therapeutic strategies and emerging directions aimed at overcoming resistance and improving clinical efficacy. Full article

Mitochondria serve as an essential component in the maintenance of cardiac function, and targeting them may represent a promising approach to handling heart failure (HF). HF in this review refers to various etiologies, including ischemic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy, unless otherwise specified. Mitochondrial dysfunction, a distinctive feature of HF, leads to a progressive decrease in bioenergetic reserves due to switching of energy production from oxidation of fatty acids in mitochondria to glycolytic pathways. The main problem in developing methods to improve mitochondrial function lies in the fact that protein preparations injected through the bloodstream cannot enter cells through the plasma membrane. Modern gene therapy involving the delivery of missing genes to cells using adeno-associated virus (AAV) vectors has the potential to improve the function of cardiomyocytes (CMCs). This type of therapy aims to target proteins that have been lost, damaged, or altered due to pathological conditions in the myocardium. This review summarizes pathophysiological mechanisms associated with mitochondrial dysfunction, which is mainly caused by increased oxidative stress and impaired mitochondrial biodynamics under HF progression. It also addresses possible ways to modulate these processes using gene therapy. Special attention is paid to modern characteristics of AAVs that can be used as vectors for the efficient delivery of desired genes to CMCs. Full article

Human papillomavirus (HPV) infection is a leading cause of cervical cancer and a significant contributor to anogenital and oropharyngeal malignancies worldwide. While the oncogenic functions of HPV oncoproteins E6 and E7 in disrupting nuclear tumor suppressor pathways are well established, their influence on mitochondrial biology has only recently emerged as a critical facet of HPV-driven carcinogenesis. This review synthesizes current evidence on the qualitative and quantitative alterations of mitochondrial DNA (mtDNA) and their functional consequences in HPV-associated cancers. We discuss how E6 and E7 modulate mitochondrial dynamics, bioenergetics, and redox balance, contributing to metabolic reprogramming, resistance to apoptosis, and adaptation to tumor microenvironmental stress. We also examine the clinical significance of mtDNA mutations, deletions, and copy number variations as potential biomarkers for diagnosis, prognosis, and therapy response. Advances in multi-omics approaches, high-throughput sequencing, and patient-derived organoid models have accelerated the exploration of mitochondria as therapeutic targets. Integrating mitochondrial profiling into HPV-related cancer research holds promise for identifying novel metabolic vulnerabilities and guiding the development of mitochondria-directed treatment strategies. Full article

Background: Glaucoma is a chronic neurodegenerative disorder characterized by the selective vulnerability of retinal ganglion cells (RGCs), in which mitochondrial dysfunction, redox imbalance, and impaired bioenergetic signaling play central pathogenetic roles. Mitochondrial homeostasis in RGCs critically depends on maintaining intracellular NAD⁺ pools, which support oxidative phosphorylation, sirtuin-mediated deacetylation, and antioxidant gene expression. Nicotinamide riboside (NR), a potent NAD⁺ precursor, and berberine (BBR), an AMPK activator derived from Berberis aristata, have recently emerged as synergistic modulators of mitochondrial metabolism and oxidative stress resistance. Methods: This study retrospectively assessed clinical outcomes associated with combined nutraceutical supplementation of nicotinamide riboside (NR) and berberine (BBR) in patients with primary open-angle glaucoma undergoing stable topical hypotensive therapy. We have included a narrative review in the current literature regarding NAD⁺ biology, AMPK–sirtuin signaling, and oxidative stress responses in retinal ganglion cell (RGC) degeneration. Due to the absence of comparator groups receiving only NR or only berberine in this retrospective cohort, the combined supplementation has been regarded as a biologically complementary strategy, and the potential for synergistic efficacy remains a subject for further investigation. Results: Translationally, a retrospective clinical cohort receiving combined NR and BBR supplementation showed functional stabilization of the visual field and structural preservation of the retinal nerve fiber layer over a six-month follow-up, in line with the proposed mitochondrial protective mechanisms. Conclusions: The clinical trends identified in this retrospective cohort have substantiated the translational significance of NR + BBR supplementation as a potential adjunctive approach in glaucoma management. NAD⁺ repletion and engagement of the AMPK–SIRT–NRF2 pathway may enhance mitochondrial resilience in RGCs. Collectively, these findings offer initial clinical evidence advocating for additional controlled studies on NR + berberine supplementation, while mechanistic interpretations have been derived from the existing literature and are hypothesis-generating. Full article

Background/Objectives: Coenzyme Q10 (CoQ10) is crucial for mitochondrial bioenergetics and redox balance and has been studied in hearing disorders. Its clinical use ranges from genetic mitochondrial deafness to acquired hearing loss associated with oxidative stress. This review aimed to map human clinical evidence on CoQ10 in hearing issues and differentiate its therapeutic roles based on underlying causes. Methods: This review was conducted following the PRISMA Extension for Scoping Reviews (PRISMA-ScR). A systematic search of PubMed, Europe PubMed Central, the Directory of Open Access Journals (DOAJ), and ClinicalTrials.gov was performed. Human clinical studies evaluating CoQ10 or water-soluble CoQ10 formulations with hearing-related outcomes were included and synthesized descriptively. Results: Fourteen studies met the inclusion criteria, including randomized controlled trials, non-randomized clinical studies, case series, and case reports. Two distinct therapeutic roles of CoQ10 emerged: in primary mitochondrial hearing disorders caused by defects in mitochondrial DNA or CoQ10 biosynthesis pathways, CoQ10 acted as a replacement therapy and was consistently linked to stabilization or prevention of progressive sensorineural hearing loss. Conversely, in acquired or age-related conditions—including presbycusis, noise-induced hearing loss, ototoxicity, tinnitus, and sudden sensorineural hearing loss—CoQ10 was used as an antioxidant or neuroprotective supplement, with outcomes showing functional preservation, symptom reduction, or decreased cochlear injury. Internal validity varied across studies: most evidence for replacement therapy was derived from observational designs, and antioxidant applications were mainly supported by small or preliminary clinical trials. Conclusions: The available evidence suggests two distinct clinical roles of CoQ10 in hearing disorders: (i) replacement therapy in genetically defined mitochondrial deafness and (ii) adjunctive antioxidant/neuroprotective use in acquired conditions. Given heterogeneity and limited study quality, further well-designed trials are needed before broad clinical recommendations can be made. Full article

Neurodegenerative diseases (NDs) are the most prevalent age-associated disorders, characterized by progressive neuronal loss and cognitive decline. Mitochondrial dysfunction is strictly associated with NDs and represent one of the hallmarks of these disorders, with neurological syndromes frequently representing the primary clinical manifestations of mitochondrial abnormalities. As central regulators of cellular bioenergetics, mitochondria play a pivotal role in both the physiological maintenance and pathogenesis of disease by different regulatory approaches. One of these, microRNAs (miRNAs), a class of small non-coding RNAs, are well-established regulators of gene expression across different biological pathways. These miRNAs were usually investigated within the cytoplasmic context, but recent discoveries have revealed the presence of these miRNAs in different parts of mitochondria, where they contribute to the regulation of gene expression and metabolic activity. These mitochondrial-localized miRNAs, termed mito-MiRNA, may originate from either nuclear or mitochondrial genomes and have been shown to modulate the translational machinery of the cells. Despite extensive research on cytoplasmic miRNAs, the functional roles of mito-MiRNA remain poorly understood, particularly in the context of neurodegenerative disorders. Based on these findings, this review aims to synthesize emerging evidence on the involvement of mito-MiRNA in in one of most prevalent neurodegenerative diseases—Parkinson’s disease (PD). Full article