Search Results (212)

Mitochondria and peroxisomes are critical for hepatic energy metabolism, lipid homeostasis, and reactive oxygen species (ROS) detoxification. In chronic hepatitis C virus (HCV) infection, continuous injury leads to cirrhosis; however, the spatial arrangement and reversibility of organelle dysfunction remain poorly understood. This study aimed to examine the zonal distribution of mitochondrial and peroxisomal injury in liver biopsies and elucidate the role of circulating cell-free mitochondrial DNA (ccfDNA) in patients with chronic HCV and cirrhosis following antiviral therapy. We employed advanced microscopy imaging and transcriptomic analysis of liver biopsies and quantified ccf-mtDNA as a noninvasive marker of mitochondrial injury in the peripheral blood of these patients. Transcriptomic data revealed alterations in mitochondrial and peroxisomal pathway alterations in HCV-infected patients. The imaging data displayed distinct zone-specific patterns of organelle damage. Following viral removal, significant improvement in mitochondrial and peroxisomal protein expression were noted, indicating partial recovery of organelle integrity following viral clearance; whether this reflects true subcellular regeneration or an early stage of a longer recovery process remains to be determined. Additionally, we showed that ccf-mtDNA quantitatively reflects intrahepatic mitochondrial dysfunction, indicating its potential as a diagnostic biomarker in therapeutic approaches. These findings indicate that organelle injury in chronic HCV is spatially patterned, disease severity-dependent, and partially reversible following antiviral therapy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF) frequently coexist within a shared cardiometabolic environment, yet their mitochondrial abnormalities are stage- and phenotype-dependent rather than uniform. In MASLD, mitochondrial adaptation evolves from increased oxidative metabolism in early steatosis toward impaired respiratory flexibility, oxidative stress, and defective quality control with disease progression, whereas the failing myocardium develops reduced energetic reserve and altered substrate utilization. These organ-specific disturbances can modify mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, stress-responsive endocrine mediators, and extracellular vesicle-associated mitochondrial cargo. However, similar mitochondrial abnormalities or circulating signals in the liver and heart do not by themselves establish direct inter-organ communication. This review distinguishes shared systemic drivers and organ-intrinsic mitochondrial stress from source-resolved cardio-hepatic signaling, highlighting hepatic ketogenesis, fibroblast growth factor 21 (FGF21), mitochondrial DNA (mtDNA)-dependent inflammatory pathways, and extracellular vesicle-mediated cargo transfer as mechanistically distinct examples with different levels of evidence. We further discuss biomarker limitations, HF-related hemodynamic liver injury, and therapeutic strategies ranging from established cardiometabolic unloading to emerging mitochondria-centered interventions. A stage-, phenotype-, and source-resolved framework may improve interpretation of mitochondrial signals and guide future mechanistic and translational studies in the MASLD–HF overlap. Full article

Cardiac involvement in systemic sclerosis (SSc) is mechanistically heterogeneous, driven by concurrently operative processes spanning right ventricular dysfunction, pulmonary microvascular remodeling, and mitochondrial damage. The existing literature rarely synthesizes these domains simultaneously, leaving substantive gaps in mechanistic understanding and the clinical management of SSc cardiac disease. An integrative review of original primary research was conducted using PubMed, Scopus, and Web of Science. Search terms combined “systemic sclerosis,” “right ventricular dysfunction,” “echocardiographic strain,” “pulmonary microvascular disease,” “nailfold capillaroscopy,” “mitochondrial dysfunction,” “oxidative stress,” and “cardiac biomarkers.” Eligible articles were required to report original empirical findings in SSc or SSc-related pulmonary arterial hypertension populations, encompassing echocardiographic, microvascular, molecular, or biomarker outcomes. Right ventricular function is compromised across multiple echocardiographic dimensions—from an elevated myocardial performance index and impaired ventriculoarterial coupling to prognostically significant speckle-tracking strain abnormalities—independent of overt pulmonary hypertension. Pulmonary microvascular disease, quantified by nailfold capillaroscopy and flow-mediated dilation, correlates directly with cardiac magnetic resonance tissue characterization in SSc-related pulmonary arterial hypertension. Mitochondrial dysfunction involving respiratory chain impairment, abnormal fusion dynamics, and altered mitochondrial DNA (mtDNA)copy number is demonstrable across dermal fibroblasts, monocytes, and immune cell populations. Circulating cardiac biomarkers complement echocardiographic findings and predict cardiopulmonary mortality. The integrative framework linking right ventricular remodeling, peripheral vasculopathy, and mitochondrial injury offers substantially richer insight into SSc cardiac pathophysiology than any single-domain perspective can provide, with direct implications for early detection and therapeutic targeting. Full article

Obesity-associated metabolic disorders are characterized by impaired glucose and lipid metabolism, insulin resistance, and adipose tissue dysfunction. Interferon regulatory factor 1 (IRF1) is a transcription factor primarily involved in immune regulation; however, its role in adipocyte metabolic regulation remains incompletely understood. In this study, adipocyte-specific Irf1 knockout (Irf1 AKO) mice were generated using the Cre/loxP system and subjected to either a regular chow diet or a high-fat diet (HFD). Metabolic phenotyping, insulin signaling analysis, mitochondrial homeostasis-related assessment, and in vitro adipocyte experiments were performed. Adipocyte-specific IRF1 deficiency improved insulin-stimulated AKT phosphorylation in white adipose tissues and enhanced glucose tolerance and insulin sensitivity under HFD conditions. These metabolic improvements were accompanied by reduced oxygen consumption, energy expenditure, heat production, β3-adrenergic-induced lipolytic response, and cold tolerance. At the molecular level, IRF1 deficiency was associated with reduced TOMM20 expression, decreased mtDNA content, downregulation of oxidative phosphorylation-related genes, and reduced ATP levels in adipose tissues, suggesting altered mitochondrial homeostasis. In 3T3-L1 adipocytes, IRF1 knockdown increased insulin-stimulated AKT activation, glucose uptake, and lipid accumulation, whereas IRF1 overexpression showed opposite trends. Collectively, these findings suggest that adipocyte IRF1 is associated with insulin signaling, lipid metabolic remodeling, and mitochondrial homeostasis, and highlight a potential dissociation between improved insulin responsiveness and reduced energy expenditure in diet-induced obesity. Full article

Timeless and its fission yeast ortholog Swi1 are evolutionarily conserved components of the replication fork protection complex that ensures faithful DNA replication and genome stability. While their nuclear roles are well-characterized, their roles in mitochondrial genome maintenance remain unknown. Here, we demonstrate a previously unrecognized connection between Timeless/Swi1 and mitochondrial homeostasis. In fission yeast, swi1 deletion increased association of the DNA repair protein Rad52 with mitochondrial DNA sequences across the mitochondrial genome, suggesting altered mitochondrial genome maintenance. Unexpectedly, swi1∆ cells showed an increased mtDNA copy number and improved growth under respiratory conditions, suggesting activation of compensatory mechanisms that promote mitochondrial genome maintenance. The loss of Swi1 also partially rescued the growth defect under respiratory conditions and mtDNA loss associated with depletion of mitochondrial DNA polymerase γ, linking Swi1 to pathways regulating mitochondrial replication under stress. Consistent with these phenotypes, transcriptomic and pathway enrichment analyses revealed transcriptional changes indicative of reduced glycolysis and enhanced oxidative phosphorylation, suggesting a shift toward respiratory metabolism. In human cells, Timeless depletion elicited distinct mitochondrial responses depending on the cell type. While Timeless-depleted TE-11 and Saos-2 cells elicited mitochondrial phenotypes comparable to those observed in fission yeast, Timeless depletion in U-2 OS cells led to reduced mtDNA copy number, elevated mitochondrial reactive oxygen species, and decreased mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Despite these phenotypic differences, both fission yeast and human cells exhibited elevated levels of orthologs of the mitochondrial transcription factor A (TFAM) and the oxidative stress regulator NRF2, suggesting the conserved activation of compensatory mitochondrial and antioxidant pathways. Together, these findings identify an evolutionarily conserved connection between Timeless/Swi1 and mitochondrial homeostasis and reveal distinct adaptive responses to mitochondrial stress. Full article

Background: Cordyceps polysaccharides (CSP) have shown neuroprotective potential in models of ischemic stroke, but the underlying mechanisms remain to be clarified. Methods: In this study, the effects of CSP were evaluated in MCAO rats and OGD-exposed BV-2 cells. Results: CSP significantly attenuated ischemic injury and inflammatory responses in both in vivo and in vitro models. Mechanistically, CSP decreased CMPK2 expression, increased TFAM levels, and reduced 8-OHdG expression, suggesting attenuation of oxidative DNA damage and mitochondrial DNA-associated stress. EdU staining further showed that OGD-induced DNA synthesis-related signals were predominantly extranuclear, supporting the possibility of mtDNA-associated alterations under ischemia-like conditions. Moreover, CSP suppressed the upregulation of NLRP3, Caspase-1, N-GSDMD, IL-1β, and IL-18, and reduced LDH release following OGD exposure, suggesting inhibition of inflammasome-associated pyroptotic signaling. Conclusions: These findings suggest that the neuroprotective effects of CSP in ischemic stroke models may be related to the modulation of CMPK2/mtDNA/NLRP3 inflammasome pathway and reduced pyroptosis. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial metabolic disorder that is strongly associated with mitochondrial dysfunction and oxidative stress, which may potentially compromise the integrity of mitochondrial DNA (mtDNA). However, the role of the base excision repair (BER) pathway—the main mechanism responsible for repairing oxidative lesions in mitochondria—and maintaining mtDNA stability in MASLD remains poorly understood. Here, we analyzed total mRNA expression levels of key BER components in whole-blood samples, along with mitochondrial protein levels of the selected components. Additionally, we assessed the mtDNA copy number and the damage of mtDNA and nuclear DNA in peripheral leukocytes from MASLD patients and healthy controls. We found that MASLD patients differed from controls in mtDNA and nuclear DNA damage, mtDNA copy number, and selected BER-related markers. However, because the MASLD and control groups also differed substantially in age and BMI, these molecular differences should be interpreted as potentially being associated with age- and BMI-related metabolic status rather than attributable to MASLD alone. While several BER-related genes were downregulated at the mRNA level, the corresponding mitochondrial protein levels were not consistently decreased in MASLD (ProteomeXchange: PXD075974), indicating a discordance between transcriptional and protein-level regulation. These results suggest that altered mitochondrial BER and mtDNA instability in peripheral leukocytes may reflect the combined influence of MASLD, aging, obesity, and broader metabolic dysfunction. Full article

Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD⁺ metabolism, and impaired pyruvate oxidation together create a cellular environment that favors persistent inflammatory activation. These signals engage NF-κB, NLRP3 inflammasome, cGAS–STING, and SASP pathways, allowing mitochondrial stress to spread from organelle dysfunction to tissue-level inflammation. Within this framework, pyruvate dehydrogenase kinase 4 (PDK4) is of particular interest because it directly controls mitochondrial pyruvate entry through inhibition of the pyruvate dehydrogenase complex. By phosphorylating and inhibiting the pyruvate dehydrogenase complex, PDK4 limits mitochondrial pyruvate oxidation and favors lactate accumulation, fatty acid utilization, and redox-inflammatory signaling. Recent work in senescent cells links PDK4-dependent lactate accumulation to NOX1-derived ROS and SASP activity, suggesting a direct route by which altered fuel handling may reinforce inflammation. Here, we review mitochondrial dysfunction as the organizing principle of age-associated meta-inflammation, discuss PDK4 as a central metabolic checkpoint, examine tissue-specific consequences in muscle, adipose tissue, brain, and kidney, and evaluate therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan. Full article

Background/Objectives: The developmental origins of health and disease (DOHaD) theory suggests that intrauterine and early postnatal life represents a critical window for programming lifelong health trajectories and disease susceptibility in offspring. Maternal nutritional imbalance during this period is closely associated with obstetric complications and an elevated risk of metabolic disorders in children. As central metabolic hubs, mitochondria constitute a critical axis linking adverse in utero exposure to metabolic defects in offspring across generations. Methods: In this narrative review, we searched PubMed and Web of Science (up to 8 July 2026) for English-language literature linking maternal metabolic conditions and mitochondrial dysfunction. We included in vivo, in vitro, and clinical studies, explicitly excluding primary inherited mtDNA mutations and nonnutritional toxicant exposures to isolate nutritional programming effects. Results: Maternal metabolic stress induces multifaceted, tissue-specific mitochondrial alterations in the developing offspring. Rather than a uniform systemic decline, mitochondrial reprogramming exhibits profound spatial and cellular heterogeneity across critical metabolic organs, including the placenta, liver, skeletal muscle, heart, and hypothalamus. These developmental adaptations often manifest as molecular compensations, such as altered mitochondrial dynamics, perturbed biogenesis, and shifted OXPHOS capacity, ultimately leading to functional bioenergetic failure, oxidative stress, and the establishment of insulin resistance. Discussion: Organ-specific mitochondrial dysfunction drives the maternal transmission of metabolic syndrome. Targeting these mechanisms via dietary modifications, exercise, pharmacological agents, and mitochondrial transplantation offers promising strategies to rescue bioenergetics and prevent metabolic diseases in offspring. Full article

Background/Objectives: DNA-based identification of degraded human remains represents a major challenge in forensic science, particularly in cases involving burned, fragmented, or commingled bodies. Advances in forensic genetics have expanded the analytical capabilities for such samples; however, the effectiveness of different approaches and their integration within Disaster Victim Identification (DVI) workflows remain heterogeneous. This systematic review aims to critically evaluate current evidence on DNA-based identification of degraded remains, focusing on methodological strategies, emerging genomic technologies, and DVI applications, while integrating laboratory evidence and operational forensic practice into a structured analytical framework. Methods: A systematic literature search was conducted in Scopus and Web of Science from database inception to 5 June 2026, following PRISMA 2020 guidelines. Eligible studies included original research addressing DNA analysis of degraded, thermally altered, or highly compromised human remains in forensic or DVI contexts. After a multistep screening process involving title/abstract and full-text evaluation, 37 studies were included. Data were extracted and organized into three thematic categories: (i) core DNA analysis, (ii) advanced molecular technologies, and (iii) DVI case applications. Results: The findings demonstrate that DNA recovery from degraded remains is influenced by thermal exposure, tissue type, and sampling strategy. Teeth and dense cortical bone consistently provide higher DNA yield. While autosomal STR profiling remains the primary analytical approach, its limitations in highly degraded samples are mitigated through the complementary use of mitochondrial DNA (mtDNA), Y-chromosome STRs (Y-STRs), and SNP markers, together with advanced sequencing technologies such as massively parallel sequencing (MPS). Emerging technologies, including rapid DNA systems and predictive models based on macroscopic indicators, significantly enhance efficiency and success rates. DVI studies report identification rates exceeding 90–95% when multidisciplinary and structured workflows are applied. The evidence further supports a flexible triage-based analytical strategy, in which marker selection is guided by tissue preservation and degradation level. Conclusions: DNA-based identification of degraded human remains has evolved into an adaptive, multi-level forensic process. Successful outcomes rely on the integration of optimized sampling, hierarchical genetic analysis, and coordinated DVI strategies. The findings support a triage-based framework that links tissue selection, degradation assessment, and analytical methodology to maximize identification success. Future developments should focus on predictive models, advanced genomic tools, and standardized workflows to further improve identification in challenging forensic scenarios. Full article

Microplastics (MPs) can adsorb and transport heavy metals, but their influence on cadmium (Cd)-induced hepatotoxicity in mammals remains unclear. Forty-eight male Kunming mice were assigned to control, Cd, MP, and Cd + MP groups and exposed by oral gavage for 42 days. Growth performance, liver injury, oxidative stress, and inflammation were assessed, and transcriptomic and metabolomic analyses were integrated with qPCR, mitochondrial DNA (mtDNA) copy number, and ATP measurements. Compared with Cd alone, combined exposure resulted in greater reductions in body weight gain, the liver index, and antioxidant enzyme activities, together with more severe hepatic lesions and higher levels of liver injury markers and inflammatory cytokines. Co-exposure also induced broader transcriptional and metabolic disturbances than Cd alone. Integrated omics analyses converged on the dysregulation of AMPK–FOXO signaling and related energy metabolic processes. qPCR confirmed more pronounced alterations in pathway-related genes after co-exposure, while reductions in mtDNA copy number and ATP content indicated aggravated mitochondrial dysfunction and impaired energy metabolism. Collectively, these results demonstrate that MPs exacerbate Cd-induced liver injury and suggest that disruption of AMPK–FOXO-associated energy metabolism is a key molecular feature underlying the enhanced hepatotoxicity observed under combined exposure. Full article

Circadian disruption has been linked to impaired male fecundity, but its association with semen molecular phenotypes and circadian genes remains unclear. We analyzed 441 men from the Male Reproductive Health in Chongqing College Students cohort to assess whether social jetlag, an indicator of circadian disruption, was associated with whole-semen mitochondrial DNA copy number (mtDNAcn), an emerging biomarker of male fecundity. Core circadian genes related to mtDNAcn were screened using genetic polymorphism data. A light-cycle phase-shifting mouse model, Cry1-knockout mice, and testicular Cry1 re-expression models were used for experimental validation, with histology, transcriptomics, single-cell data, and proteomics analyses used to explore mechanisms. Social jetlag was associated with higher mtDNAcn in men (1.29-fold, p = 0.026), with a concordant increase in circadian-disrupted mice (1.33-fold, p = 0.010). Among core circadian genes, CRY1 showed the strongest association with mtDNAcn (p = 0.048). Cry1 knockout elevated mtDNAcn (2.18-fold, p < 0.001), whereas testicular Cry1 re-expression reduced it toward wild-type levels. Circadian disruption and Cry1 deficiency were accompanied by seminiferous epithelial disorganization, spermatogenesis-related transcriptomic changes, and altered mitochondrial pathway signatures. To our knowledge, this study is the first to identify whole-semen mtDNAcn as a circadian-disruption-associated molecular phenotype and supports CRY1 as a candidate regulator. Full article

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction-associated steatohepatitis (MASH) arise in the setting of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This review examines how mitochondrial dysfunction participates in the transition from lipid accumulation to hepatocyte injury, inflammation, and fibrosis, and how evidence from human, animal, and in vitro studies should be interpreted. Methods: We provide a narrative synthesis of mechanistic, translational, and clinical studies on hepatic mitochondrial metabolism, fatty acid oxidation, oxidative phosphorylation, redox stress, organelle crosstalk, mitophagy, mitochondrial biogenesis and proteostasis, mitochondrial danger signals, the gut-liver-mitochondria axis, and mitochondria-related therapeutic strategies. Results: In early metabolic overload, mitochondrial oxidation may increase as an adaptive response. With persistent substrate pressure, this adaptation can become inefficient, with impaired fatty acid disposal, less efficient oxidative phosphorylation, reactive oxygen species production, redox imbalance, defective mitochondrial quality control, altered mitochondrial biogenesis, mitochondrial unfolded protein response (UPRmt)-related proteostatic stress and mtDNA instability. Mitochondrial DNA and RNA released from damaged organelles may also activate cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), inflammasome, and RNA-sensing pathways, linking hepatocyte stress to macrophage activation, stellate cell activation, extracellular matrix deposition, and fibrosis. Conclusions: The current evidence supports mitochondria as a stage-dependent amplifier of metabolic liver injury rather than a uniform initiating event. Clinically, the strongest evidence remains with upstream metabolic unloading and liver-directed metabolic therapy, whereas direct mitochondrial restoration and quality-control targeting remain promising but less mature. Full article

Mitochondrial alterations, including mitochondrial DNA (mtDNA) loss and defects in maintenance pathways, have been recognized as an important driver for toxic effects of environmental pollutants. Therefore, exposure to nano-sized particles (1–100 nm in diameter; a new source of environmental pollution) may also result in these mitochondrial impairments; however, controversial results have been reported. Available studies collected from three electronic databases through July 2025 were pooled for a comprehensive assessment. Meta-analysis of 19 in vitro studies (69 datasets) showed exposure to nano-sized particles significantly reduced mtDNA content [standardized mean difference = −1.08; p-value = 0.001). The expression levels of mtDNA-encoded (ND1, COX1,2, CYTB, ATP6), mitochondrial biogenesis (SIRT1, PGC-1α, TFAM) and fusion genes (MFN1, MFN2, OPA1) were found to be significantly down-regulated, while fission genes DRP1 and FIS1 were up-regulated following nano-sized particle exposure after meta-analysis of corresponding in vitro and in vivo studies. Accordingly, mtDNA depletion and expression disruption in mtDNA-encoded and maintenance genes may represent important contributors to nano-sized particle exposure-induced diseases. Full article

Mitochondrial dysfunction has been increasingly implicated in the pathobiology of neurodevelopmental conditions, particularly autism and attention-deficit/hyperactivity disorder (ADHD). Because the developing brain is critically dependent on sustained ATP production, impairments in oxidative phosphorylation, mitochondrial dynamics, and redox balance may disrupt neuronal maturation, synaptic development, and neural circuit refinement during sensitive developmental periods. This review examines evidence from postmortem neurochemistry, genomics, magnetic resonance spectroscopy, and biomarker research to characterize mitochondrial impairment across autism and ADHD. Studies in autism report an elevated burden of heteroplasmic mitochondrial DNA (mtDNA) variants, along with alterations in mtDNA copy number, respiratory chain capacity, fission–fusion dynamics, and antioxidant defenses. Postmortem data demonstrate reduced activity of electron transport chain Complexes I, III, and V in the frontal cortex, temporal lobe, and cerebellum. These bioenergetic abnormalities are accompanied by elevated oxidative stress markers alongside mitochondria-mediated immune activation. In vivo neuroimaging corroborates these findings through elevated cerebral lactate and reduced phosphocreatine-to-ATP ratios. Evidence in ADHD is limited, but similarly implicates mitochondrial dysfunction, consistent with the frequent co-occurrence of these conditions and their partially shared architecture. The available literature supports mitochondrial dysfunction as a transdiagnostic biological feature of neurodevelopmental conditions, with relevance to mechanistic biomarker identification and targeted therapeutic development. Full article