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PubMed2026

CHCHD10 Mitigates Alzheimer's Disease-Related Phenotypes in Association With Epigenetic Remodeling in Directly Reprogrammed Neurons.

Mitochondrial dysfunction and chromatin dysregulation are interconnected contributors to neuronal vulnerability in Alzheimer's disease (AD), yet the molecular mechanisms linking these processes remain poorly understood. CHCHD10, a mitochondrial intermembrane space protein, has been implicated in neurodegenerative disorders, but its role in AD has not been defined. Here, we identify CHCHD10 as a previously unrecognized modulator of neuronal epigenomic stability in AD. Using direct fibroblast-to-neuron reprogramming, which preserves patient-specific epigenetic signatures, we show that AD neurons recapitulate genome-wide hypomethylation patterns observed in postmortem AD cortex. CHCHD10 expression is significantly reduced in AD neurons and across multiple human brain datasets, including single-cell and bulk RNA sequencing, proteomics, and human cortical tissue analyses. Restoration of CHCHD10 in AD neurons reduces amyloid-β and insoluble tau accumulation while reversing AD-associated differentially methylated regions across CpG islands, promoters, and regulatory elements. CHCHD10-responsive methylation changes overlap with those observed in human AD brain regions and colocalize with significant AD loci and cortex-specific eQTL loci, including MAPT and ABCA7. Finally, we identify KATNAL2 as a CHCHD10-responsive effector whose loss enhances tau phosphorylation and seeding, whereas its restoration mitigates tau pathology. Together, these findings support a CHCHD10-associated neuroprotective pathway linking mitochondrial dysfunction, epigenomic instability, and tau pathology in AD.

Humans↗

PubMed2025

MLL1 downregulation drives hair cell ferroptosis via mitochondrial and endoplasmic reticulum stress mechanisms through PERK-eIF2α-ATF4-Chop and PI3K/Akt-Lrp1 signaling pathway.

BACKGROUND: Sensorineural hearing loss is characterized by irreversible hair cell (HC) degeneration. Ferroptosis, which is marked by the accumulation of reactive oxygen species and elevated levels of lipid peroxidation products, has been shown to contribute to drug-mediated auditory impairment. This study aimed to elucidate the role of mixed-lineage leukemia 1 (MLL1) in HC survival in the auditory system. METHODS: The HEI-OC1 auditory cell line and postnatal cochlear explants were evaluated using MM-102, a specific MLL1 histone methyltransferase inhibitor. Western blotting, quantitative polymerase chain reaction, electron microscopy, and immunofluorescence were used to elucidate the role of MLL1 in regulating ferroptosis in HC injury. RNA sequencing (RNA-seq) was used to analyze the molecular mechanisms of MLL1 intervention in HC injury from an epigenetic perspective. RESULTS: Our findings demonstrated that immunofluorescence staining revealed a crucial role of MM-102 in promoting intracellular accumulation of lipid peroxides and ferrous ions. Subsequent analysis showed MLL1 downregulation-induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress, with transmission electron microscopy imaging confirming ultrastructural alterations in mitochondria and ER. Mechanistic investigations identified the PERK-eIF2α-ATF4-Chop signaling axis as the regulatory pathway, evidenced by Western blotting quantification of phosphorylated PERK (p-PERK), ATF4, and Chop levels. RNA-seq analysis revealed 741 differentially expressed genes (335 upregulated and 406 downregulated). Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis specifically highlighted significant enrichment of the PI3K/Akt-Lrp1 pathway, with corresponding activation patterns of phospho (p)-Akt and Lrp1 confirmed through Western blotting analysis. CONCLUSIONS: MLL1 downregulation initiates ferroptosis in cochlear HCs. This process is intrinsically associated with the activation of mitochondrial dysfunction and ER stress. The study highlights the importance of MLL1 in HC survival, suggesting its potential as a therapeutic target for treating hearing loss.

Endoplasmic Reticulum Stress↗

PubMed2025

Targeting the bile acid receptor TGR5 with Gentiopicroside to activate Nrf2 antioxidant signaling and mitigate Parkinson's disease in an MPTP mouse model.

INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by classical symptoms including bradykinesia, rest tremor and rigidity. Oxidative stress and mitochondrial dysfunction are recognized as pivotal factors in PD progression. Gentiopicroside (GPS), a secoiridoid derived from Gentiana manshurica Kitagawa, exhibits antioxidant and mitophagy induction properties. Nonetheless, the effects and mechanisms by which GPS mitigates neurodegeneration in PD remain to be thoroughly elucidated. OBJECTIVES: The goal of this study was to investigate the neuroprotective effects and mechanisms of GPS in PD models. METHODS: We established the MPTP/MPP+-induced PD models to measure the neuroprotection of GPS. Transcriptomic analysis, oxidative biochemical kits, western blot and cell immunofluorescence were conducted to elucidate the fundamental mechanisms at play. Subsequently, the targeting and activation of the transmembrane G protein-coupled receptor-5 (TGR5) by GPS were measured by molecular docking, cellular thermal shift assay, microscale thermophoresis (MST) and cyclic adenosine monophosphate (cAMP) quantitation. Finally, we verified whether the neuroprotective and antioxidant effects of GPS were dependent on TGR5 by using specific small interfering RNA (siRNA), pharmacological antagonist and knockout mice. RESULTS: GPS significantly attenuated dopaminergic (DAergic) neuron loss and restored motor function in the MPTP-induced PD mouse model. Whole-genome RNA sequencing and subsequent mechanistic investigations revealed that GPS enhanced the expression and facilitated nuclear entry of factor erythroid-related 2-factor 2 (Nrf2), and reduced oxidative stress and mitochondrial dysfunction stimulated by neurotoxin. Additionally, GPS could target TGR5 and prevent its downregulation in PD model. TGR5's silencing or inhibition weakened the neuroprotective effect of GPS and blocked GPS-mediated activation of Nrf2 antioxidant signaling in PD model. Moreover, the therapeutic effect of GPS in mitigating motor deficits and neurodegeneration was also abolished in Tgr5 knockout mice. CONCLUSION: These findings collectively indicated that GPS targeted TGR5 to activate Nrf2 antioxidant signaling and ultimately ameliorated the pathological progression of PD.

Animals↗

PubMed2026

Spatial niche remodeling of senescent liver-resident immune cells and its role in chronic liver diseases.

The liver serves the triple functions of metabolism, detoxification, and immune surveillance. Its unique immune microenvironment is shaped by continuous exposure to gut-derived antigens, pathogen-associated molecular patterns (PAMPs), and metabolites arriving via the portal vein, necessitating a delicate equilibrium between immune tolerance and effector activation. This equilibrium relies on the coordinated activities of diverse liver-resident immune cell populations-including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), dendritic cells (DCs), tissue-resident memory T cells (TRM), innate-like T cells, including mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδ T cells, innate lymphoid cells (ILCs, encompassing conventional NK cells and helper ILC subsets), and neutrophils. With advancing age and chronic injury, these resident immune cell populations undergo profound senescence-associated phenotypic reprogramming that is spatially organized along the portal-to-central axis of the hepatic lobule. Key mechanisms include: telomere dysfunction and DNA damage accumulation driving persistent activation of p53/p21 and p16/Rb pathways; mitochondrial dysfunction with mitochondrial DNA (mtDNA) leakage fueling the senescence-associated secretory phenotype (SASP) via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; epigenetic age acceleration, including genome-wide H3K27me3 heterochromatinization; and metabolic reprogramming toward glycolysis and lipid accumulation. This review proposes a "spatial niche remodeling" framework to integrate these cell-intrinsic senescence programs with their lobular context, intercellular communication network rewiring, and pathogenic roles across the spectrum of chronic liver disease-from steatosis through steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. We critically evaluate emerging senotherapeutic strategies targeting specific liver-resident immune cell subsets, discuss the barriers to clinical translation, and identify priority areas for future investigation, including the application of spatial multi-omics, humanized models, and epigenetic clock-guided clinical trials.

Kupffer cells↗

PubMed2025

Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration.

Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene FOXRED1, a specific assembly factor for complex I, cause mitochondrial dysfunction; however, their role in DEE pathogenesis remains unexplored. Clinical data and peripheral blood mononuclear cells (PBMCs) were obtained from two patients with compound heterozygous FOXRED1 mutations (c.850T>C (p.C284R)/c.1054C>T (p.R352W) and c.1054C>T (p.R352W)/c.3dup (p.I2Dfs*35) and age-matched controls. Mitochondrial phenotyping, included complex I activity, mitochondrial respiration stress test, membrane potential, intracellular ROS, and NAD+/NADH ratio, were performed. Both patients exhibited early-onset refractory seizures, basal ganglia lesions, hyperlacticemia, and developmental regression. FOXRED1 mutations resulted in 50% reduction in complex I activity, dissasembly of complex I, mitochondrial depolarization, oxidative stress, and NAD+/NADH imbalance. Niacin restored the NAD+/NADH ratio in vitro, while clinical supplementation reduced blood lactate levels, suggesting it may be a potential therapeutic option.

Humans↗

PubMed2026

Kidney mitochondrial complex I dysfunction in a juvenile rat model of diabetic ketoacidosis.

BACKGROUND: The pathobiology of acute kidney injury during diabetic ketoacidosis (DKA) is not completely understood. We hypothesized that mitochondrial function is impaired during DKA as a mechanism of acute kidney injury. METHODS: We isolated kidney samples from 4 to 5 week-old rats with normoglycemia (NG, controls; n = 7), hyperglycemia (HG; n = 5), acute DKA (DKA; n = 5), and after 24 h of DKA treatment (DKA-24; n = 5). Kidney tissue homogenates were prepared from frozen tissue for measurement of mitochondrial electron transport system (ETS) complex I + III, II + III, and IV activity and citrate synthase activity using spectrophotometry and ETS complex protein expression using Western blots. RESULTS: Mitochondrial ETS complex I + III activity (mean ± SD) exhibited a stepwise decrease from HG (113 ± 54 nmol/min/mg tissue protein) to DKA (64 ± 32; p < 0.05 compared to NG) and trended toward NG control levels (143 ± 37) in DKA-24 (135 ± 39). Mitochondrial content, including citrate synthase activity and ETS complex proteins I, II, IV, and V, did not differ between groups, except that ETS complex III increased in HG and DKA and subsequently decreased in DKA-24. CONCLUSIONS: In a juvenile rat model of DKA, increasing glycemic stress caused a reversible change in kidney mitochondrial complex I function and complex III expression. IMPACT: Acute kidney injury during diabetic ketoacidosis (DKA) increases risk of future diabetic kidney disease, but the underlying pathobiology is not understood. In a juvenile rat model of DKA, we found that increasing glycemic stress caused a reversible change in kidney mitochondrial complex I function and complex III expression. These data support further investigation to determine if mitochondrial dysfunction may contribute to DKA-related acute kidney injury.

Letter↗

PubMed2025

Insights into the heterogeneity of oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a rare, adult-onset, autosomal dominant myopathy characterized by variability in the age of onset and disease progression. However, its pathogenesis and phenotypic variability remain poorly understood. The disorder is caused by an expansion of a short polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1) gene. This study presents data from 23 patients across 19 Greek families with pathogenic PABPN1 expansions, including demographic and laboratory data, as well as molecular and electron microscopy findings. Eight distinct trinucleotide expansion genotypes were identified. Electron microscopy consistently demonstrated mitochondrial abnormalities, including swelling, disrupted cristae and atypical lipid inclusions. Clinical heterogeneity was observed at both inter- and intrafamilial levels, and milder phenotypes were generally linked to smaller alleles. Notably, maternally inherited expansions were associated with an earlier disease onset and more severe progression in affected offspring. Given the genetic variability observed in the cohort, the presence of a founder effect could not be supported. A significant degree of underdiagnosis or diagnostic delay was noted, largely attributable to the rarity and clinical heterogeneity of the disease. The observed intrafamilial heterogeneity - particularly in maternally inherited expansions - supports previous reports suggesting that mitochondrial dysfunction may contribute to transgenerational disease progression in the context of a dominant, causative nuclear variant.

Humans↗

PubMed2026

Normoalbuminuric and albuminuric diabetic kidney disease exhibit divergent renal proteomic characteristics: implications for management.

BACKGROUND: The pathogenesis of diabetic kidney disease (DKD) is complex. Normoalbuminuric diabetic kidney disease (NADKD) is a special subtype of DKD that often progresses insidiously without detectable albuminuria, posing diagnostic and therapeutic challenges. Its pathogenesis remains unclear. Proteomic analysis of renal tissues may offer insights into its pathogenesis and identify biomarkers. METHODS: Clinicopathological data from 295 biopsy-proven DKD patients were collected and classified into normoalbuminuric (UACR < 30 mg/g, n = 25), microalbuminuric (UACR 30-300 mg/g, n = 26), and macroalbuminuric (UACR > 300 mg/g, n = 244) groups. Laser microdissection combined with mass spectrometry (LMD/MS) was used to analyze glomerular and proximal tubule proteomics in 5 patients per DKD subgroup and 5 control subjects. Associations with clinical features were examined. RESULTS: Glomerular proteomic analysis revealed that oxidative stress and metabolic pathways (UQCRC1) were upregulated in NADKD group, whereas the complement and coagulation cascades (C3, C5, C6, C9, CFH, CFHR1) were significantly upregulated in the microalbuminuric and macroalbuminuric DKD groups. The proximal tubule proteomics analysis showed that oxidative phosphorylation-related proteins (SDHA, CYCS, UQCRQ) were upregulated in NADKD, and collagen I related proteins (COL1A1, COL1A2) were significantly upregulated. CONCLUSION: Oxidative stress and mitochondrial dysfunction are involved in the progression of NADKD, lesions predominantly located in the tubulointerstitium. The complement pathway participates in the pathogenesis and progression of albuminuric DKD (ADKD). These divergent molecular profiles suggest that NADKD and ADKD may reflect different pathophysiological mechanisms and have important implications for therapeutic strategies in diabetes management.

Humans↗

PubMed2026

Selective Inhibition of DNA Polymerase Proofreading: A Metabolic-Fidelity Mechanism Explains Agent Orange-Associated Myelodysplasia.

We performed a focused review to better understand the pathogenesis of Agent Orange (AO)-associated myelodysplastic syndrome (MDS). We first examined the mechanisms underlying conventional (de novo) MDS, a clonal hematopoietic neoplasm that typically develops in later life, and integrated these findings with our recent analysis of obesity-associated carcinogenesis. Accordingly, we propose that genomic instability in de novo MDS results from selective inhibition of the DNA polymerase proofreading exonuclease. In obesity-associated carcinogenesis, impaired AMP-activated protein kinase (AMPK) activity disrupts mitochondrial ATP production, increasing intracellular AMP concentrations. Elevated AMP selectively inhibits the proofreading exonuclease while preserving polymerase activity, allowing replication errors to escape correction and become fixed as somatic mutations. Molecular studies demonstrate that AO-associated MDS exhibits essentially the same mutational profile as de novo disease despite arising after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in young, otherwise healthy military personnel. Because TCDD is highly lipophilic, it accumulates in adipose tissue and is released slowly over decades, producing sustained mitochondrial dysfunction, reduced ATP synthesis, and chronic elevation of intracellular AMP. We propose that this metabolic disturbance converges on the same endpoint-selective inhibition of the proofreading exonuclease-thereby promoting mutagenesis and clonal evolution. Recent studies further strengthen the central role of proofreading by demonstrating that many mutations, including many found in MDS, previously attributed to spontaneous cytosine deamination, instead arise from DNA polymerase misincorporation of thymidine opposite cytosine, particularly at CpG dinucleotides, emphasizing the critical importance of fully active proofreading in preventing such misincorporations from accumulating as mutations in the genome of the cell.

AMP↗

PubMed2026

Adaptive and degenerative mitochondrial remodeling define distinct redox states in age-related macular degeneration.

Age-related macular degeneration (AMD) is associated with mitochondrial dysfunction and oxidative stress, yet the relationship between mitochondrial remodeling, redox homeostasis, and disease progression remains poorly understood. Nonhuman primates (NHPs) develop spontaneous AMD-related phenotypes, including punctate deposits and soft drusen, providing a unique animal model to investigate mitochondrial pathology in the aging retinal pigment epithelium (RPE). We integrated quantitative mitochondrial ultrastructural profiling with flavoprotein fluorescence imaging, plasma metabolomics, and whole-exome sequencing to characterize mitochondrial and redox alterations in aged rhesus macaques with AMD-related lesions. Flavoprotein fluorescence imaging demonstrated increased metabolic heterogeneity in eyes with soft drusen, consistent with altered mitochondrial redox states and oxidative stress. Morphometric analysis identified distinct mitochondrial remodeling patterns across phenotypes. Normal aging was characterized by concentric cristae and type I paracrystalline inclusions. Eyes with punctate deposits exhibited increased mitochondrial fusion-associated morphology, hyperbranching, and type I paracrystalline inclusions, consistent with a stress-responsive mitochondrial remodeling pattern. In contrast, eyes with soft drusen exhibited reduced fusion-associated morphology, reduced structural complexity, and ultrastructural features consistent with mitochondrial deterioration. These ultrastructural patterns were accompanied by distinct plasma metabolomic signatures. Punctate deposits were associated with altered glycolytic, tricarboxylic acid cycle, and redox-buffering metabolites, consistent with differences in stress-responsive metabolism, whereas soft drusen exhibited metabolomic signatures consistent with altered redox homeostasis. Whole-exome sequencing identified a mitochondrial DNA variant, MT:9582G > A, in cytochrome c oxidase subunit III (COX3) associated with the drusen phenotype. Collectively, these findings identify distinct mitochondrial remodeling patterns associated with AMD-related phenotypes in aged rhesus macaques. The convergence of ultrastructural, imaging, metabolomic, and genetic analyses suggests that punctate deposits and soft drusen are associated with different mitochondrial and redox-related responses to chronic retinal stress. These findings provide a framework for future studies investigating mitochondrial biology and redox-driven mechanisms in AMD.

Animals↗

PubMed2026

RNA dysregulation as a determinant of aging and neurodegenerative vulnerability.

In the nervous system, aging causes deterioration of cellular and molecular processes that are associated with declines in cognition, sensory perception, and motor coordination. Aging is also the strongest risk factor for neurodegenerative disease, yet the mechanisms by which aging predisposes neurons to dysfunction remain incompletely understood. While genomic instability, proteostasis decline, mitochondrial dysfunction, and chronic inflammation have dominated prevailing models, recent evidence highlights RNA dysregulation as a central component of age-associated decline. In this review, we summarize recent findings suggesting that aging progressively erodes RNA regulatory fidelity through alterations in RNA-binding protein abundance, localization, biophysical behavior, and RNA interactions. We argue that age-dependent RNA dysregulation represents an important mechanism that converges with genetic risk to drive neuronal vulnerability and neurodegeneration.

RNA dysregulation↗

PubMed2026

Alterations of endothelial cell bioenergetics in congenital diaphragmatic hernia.

BACKGROUND: Pulmonary vascular development in congenital diaphragmatic hernia (CDH) is characterized by impaired angiogenesis and pathologic remodeling that contribute to pulmonary hypertension/hypoplasia. Mitochondria regulate endothelial energy, redox balance, and angiogenic signaling, suggesting a role in CDH vascular disease. METHODS: Endothelial cells (ECs) were isolated from umbilical veins of healthy and CDH newborns. Mitochondrial bioenergetics and glycolytic acidification were assessed by extracellular flux. Oxidative stress, mitochondrial membrane potential, and mitochondrial mass were measured by flow cytometry, while mitochondrial DNA copy number (mtDNA-CN) and morphology were evaluated by qPCR and microscopy. RESULTS: CDH ECs exhibited increased maximal respiratory capacity with elevated proton leak and reduced ATP coupling efficiency. Basal glycolytic activity was elevated. These changes were accompanied by increased mitochondrial superoxide and cellular reactive oxygen species and by severity-associated loss of membrane potential. Despite reduced MitoTracker Green, mtDNA-CN was unchanged, and confocal imaging revealed a highly branched, peripherally distributed network. CONCLUSIONS: These data define a distinct endothelial mitochondrial phenotype marked by metabolic activation, bioenergetic inefficiency, and oxidative stress, with concurrent upregulation of glycolysis and oxidative phosphorylation rather than a glycolytic shift. Structural remodeling with preserved mitochondrial content further indicates qualitative changes. Collectively, these findings link mitochondrial dysfunction to vascular pathology in CDH. IMPACT: Defines a distinct mitochondrial state in CDH endothelium, characterized by metabolic activation with inefficient oxidative phosphorylation, redox imbalance, and structural reorganization in primary human cells. Demonstrates that mitochondrial alterations in CDH occur without changes in mitochondrial content, supporting a model of qualitative remodeling. Provides rare human, cell-based data in CDH, addressing a major gap in a field largely reliant on animal models and indirect measures. Links mitochondrial alterations to clinical severity, supporting relevance to disease burden and heterogeneity. Establishes a framework for mitochondrial involvement in CDH vascular disease, with potential implications for future biomarker development and therapeutic targeting.

Journal Article↗

PubMed2026

Exercise elicits mitonuclear protein imbalance and UPRmt in the liver of mice with obesity.

Mitochondrial dysfunction plays a critical role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). It has been proposed that mitochondrial unfolded-protein response (UPRmt) activation improves mitochondrial function in the liver. Growing evidence demonstrates that physical exercise effectively prevents and treats MASLD. However, the effects of exercise on UPRmt activation in the liver are unknown. Thus, we investigated the impact of aerobic training on the mechanisms involved in mitochondrial quality control in the liver in a mouse model of obesity. Liver transcript data from a genetic reference panel of BXD isogenic mice revealed a negative correlation between UPRmt-related genes and hepatic triacylglycerol content. In addition, the liver UPRmt markers were strongly associated with several mitochondrial-related genes in the hepatic tissue of BXD mice and humans. Notably, 4 weeks of aerobic exercise strongly impacted the liver metabolism, preventing intrahepatic lipid accumulation in HFD-fed mice. Physical exercise boosted the NAD-biosynthesis pathway, elicited the mitonuclear protein imbalance, stimulated the protein content of UPRmt-markers, including CLpP, Lonp1, and Yme1L1, and improved the mitochondrial proteostasis and function in the liver in HFD-fed mice. Thus, our findings link the mitonuclear protein imbalance and UPRmt activation in the liver to mitochondrial proteostasis and MASLD prevention in response to physical exercise.

Animals↗

PubMed2026

Mitochondria-Related Pathogenic Genes in Paediatric Asthma: A Multi-Omics Mendelian Randomization Study.

Mitochondrial dysfunction is implicated in asthma pathogenesis, but causal roles of mitochondrial-related genes in paediatric asthma remain unclear. We performed a multi-omics Mendelian randomization study integrating GWAS data from paediatric asthma cohorts with blood-based methylation quantitative trait loci (mQTLs), expression QTLs (eQTLs) and protein QTLs (pQTLs) datasets. Causal inference was assessed using Summary-data-based Mendelian Randomization (SMR) and HEIDI testing, complemented by colocalization analysis. Findings were validated in independent cohorts and evaluated for tissue specificity using GTEx. Functional enrichment and protein-protein interaction (PPI) network analyses were conducted. SMR analysis identified 80 methylation sites spanning 54 genes, 26 gene expressions, and three proteins significantly associated with paediatric asthma. Colocalization analysis confirmed strong evidence for 10 methylation sites (7 genes), the STX17 eQTL (PP.H4 = 0.98) and the UNG pQTL (PP.H4 = 0.84). Tissue-specific eQTL validation replicated the STX17 association. Multi-omics integration associated ALAS1 (cg13241645, cg15698299) and TXNRD1 (cg09884423) with asthma at both methylation and expression levels, with colocalization supporting both ALAS1 associations. Furthermore, integrated mQTL-eQTL analysis suggests that DNA methylation potentially regulates ALAS1 and TXNRD1 expression. Functional enrichment and network analyses revealed that these candidate genes converge on mitochondrial metabolic pathways and identified seven hub genes with potential regulatory significance (SDHB, MFN2, GLDC, PHB2, TXNRD1, ATP5MC1 and PHB). This study provides multi-omics evidence supporting a causal role for mitochondrial-related genes, particularly ALAS1 and TXNRD1, in paediatric asthma, offering new insights into pathogenesis and potential therapeutic targets.

Humans↗

PubMed2026

TIGAR deficiency enhances cardiac resilience through epigenetic programming of Parkin expression.

Mitochondrial dysfunction devastates the heart in major cardiovascular diseases, yet the mechanisms governing mitochondrial quality control remain elusive. We discovered that TIGAR (TP53-induced glycolysis and apoptosis regulator) deficiency established profound cardiac protection through developmental epigenetic programming of Parkin expression. Using mice with whole-body and cardiomyocyte-specific TIGAR knockout, we demonstrated remarkable cardioprotection following myocardial infarction with maintained ejection fraction, and complete resistance to diet-induced cardiac hypertrophy despite comparable weight gain. TIGAR deficiency triggered dramatic increases in Parkin expression across all somatic tissues except testes, where Parkin levels remained extraordinarily high (100-fold greater than cardiac levels) regardless of TIGAR status, revealing tissue-specific regulatory mechanisms. This protection was entirely Parkin dependent, as double-knockout mice lost all cardioprotective benefits. Crucially, adult TIGAR manipulation failed to alter Parkin levels, demonstrating that this pathway operated exclusively during critical developmental windows to program lifelong cardiac resilience. Whole-genome bisulfite sequencing identified reduced DNA methylation in Prkn intron 10 as the key regulatory mechanism, with CRISPR deletion dramatically increasing Parkin expression in multiple cell lines. Our findings reveal how early cardiac metabolism programs lifelong cardiac function through epigenetic mechanisms, and identify developmental metabolic programming as a potential therapeutic target for preventing both ischemic heart disease and metabolic cardiomyopathy.

Animals↗

PubMed2026

Prioritizing Parkinson's disease risk-associated mitochondrial candidate genes via multi-omics integrative analysis.

BACKGROUND: Mitochondrial dysfunction has been implicated in Parkinson's disease (PD), but the genetically regulated mitochondrial genes associated with PD risk remain incompletely defined. METHODS: We conducted a summary-data-based genetic epidemiology study integrating summary-based Mendelian randomization (SMR), Heterogeneity in dependent instruments (HEIDI) filtering, and Bayesian colocalization to prioritize mitochondrial-related molecular features associated with PD risk. Mitochondrial-related genes were defined using MitoCarta3.0. Genetically predicted gene expression and plasma protein abundance were evaluated using expression quantitative trait loci (eQTL) data from eQTLGen and GTEx v8, and protein quantitative trait loci (pQTL) data was assessed using International Parkinson's Disease Genomics Consortium (IPDGC) as the discovery genome-wide association study (GWAS) and FinnGen as the replication dataset. Prespecified QTL analyses were interpreted using FDR correction, HEIDI filtering, and colocalization support. DNA methylation QTL analysis, mitochondrial phenotype MR, and single-nucleus RNA-seq analysis were performed as complementary analyses. RESULTS: In the primary eQTL analysis, higher genetically predicted TTC19 expression was associated with lower PD risk (OR = 0.80, 95% CI: 0.74-0.87, PPH4 = 0.80), whereas higher MALSU1 expression was associated with increased PD risk (OR = 2.21, 95% CI: 1.59-3.06, PPH4 = 0.96). Both associations survived FDR correction, passed HEIDI filtering, and showed colocalization support. GTEx whole-blood data supported the direction of the TTC19 association. No mitochondrial protein reached significance after FDR correction and colocalization filtering in the primary pQTL analysis. Complementary methylation analysis highlighted cg06270993 as an exploratory regulatory signal for MALSU1. CONCLUSIONS: This MR-colocalization study prioritizes TTC19 and MALSU1 as genetically supported mitochondrial-related candidate genes associated with PD risk. Further validation is required to define their functional roles in PD pathogenesis.

Humans↗

PubMed2026

Shielding the First 24 Postnatal Months of Life: A Proposal for a Prospective Cohort Study of Early-Life Electromagnetic Exposure and Autism Risk.

BACKGROUND: Autism Spectrum Disorder (ASD) involves Mirror Neuron System (MNS) dysfunction, driving core social and imitative impairments. Systemic physiological alterations such as autonomic dysregulation, mitochondrial dysfunction and neuroinflammation are known to impair synchronization and plasticity of neuronal clusters. A less-evident environmental cofactor, coinciding with rising ASD prevalence, is the considerable world-wide increase in electromagnetic radiation (EMR) overall exposure among children. Experimental evidence shows how low-intensity EMR influences cellular processes, via voltage-gated calcium channels (VGCCs), oxidative stress, and mitochondrial metabolism. The Resonant Convergence framework, allow to predict how chronic EMR exposure during the first 24 postnatal months of life can act as a factor in ASD pathogenesis. The best candidate mechanism is chronic Ion Cyclotron Resonance (ICR) detuning the Ca2+-calmodulin pathway, thus disrupting MNS synchronization. METHODS AND ANALYSIS: A prospective observational pilot cohort study (24-month follow-up) proposes to enroll 1000 full-term newborns into two arms: an EMR-reduced cohort (n = 500, rest and sleep-phase Faraday shielding) and a standard exposure cohort (n = 500). Exposure is quantified via radiofrequency (RF)/extremely low frequency(ELF) measurements, proximity analysis, device inventories and wearable dosimetry. The primary endpoint is a continuous neurodevelopmental trajectory score (joint attention, language, electroencephalogram (EEG) mu-rhythm); binary ASD diagnosis (Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), Autism Diagnostic Interview-Revised (ADI-R)) is a secondary, exploratory endpoint. Moreover, an optional genomic screening will evaluate gene-environment interactions within extremely low-frequency electromagnetic field (ELF-EMF) vulnerable pathways, including ASD-associated genes upregulated by RF via bromodomain and extraterminal protein (BET)-mediated epigenetic mechanisms. Analyses will employ risk ratios, Fisher's exact tests and logistic regression adjusted for confounders; mixed-effects and Bayesian modeling will evaluate longitudinal outcomes and exposure reduction effects. Given a 2-3% baseline prevalence, approximately 20-30 ASD cases are expected. The study is therefore powered for exploratory signal detection rather than definitive causal inference, providing the critical baseline data required to justify and design future confirmatory trials. Sex-stratified modeling will address the 4:1 male-to-female prevalence ratio. ETHICS AND DISSEMINATION: Ethics committee approval is not yet sought; full protocol review and approval will be obtained prior to the study initiation, in strict accordance with the Declaration of Helsinki. Written parental informed consent will be mandatory for all participants prior to enrollment. Study findings and methodological milestones will be disseminated through peer-reviewed international scientific publications. This protocol provides a structured methodological framework for the first prospective investigation of sleep-phase EMR reduction as a potential modulator of ASD incidence during early neurodevelopment. Results will inform adequately powered confirmatory trials in electromagnetic neurodevelopmental epidemiology.

autism spectrum disorder↗

PubMed2025

Integrated Multiomics Analyses of the Molecular Landscape of Sarcopenia in Alcohol-Related Liver Disease.

BACKGROUND: Skeletal muscle is a major target for ethanol-induced perturbations, leading to sarcopenia in alcohol-related liver disease (ALD). The complex interactions and pathways involved in adaptive and maladaptive responses to ethanol in skeletal muscle are not well understood. Unlike hypothesis-driven experiments, an integrated multiomics-experimental validation approach provides a comprehensive view of these interactions. METHODS: We performed multiomics analyses with experimental validation to identify novel regulatory mechanisms of sarcopenia in ALD. Studies were done in a comprehensive array of models including ethanol-treated (ET) murine and human-induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD) and human patients with alcohol-related cirrhosis and controls. We generated 13 untargeted datasets, including chromatin accessibility (assay for transposase accessible chromatin), RNA sequencing, proteomics, phosphoproteomics, acetylomics and metabolomics, and conducted integrated multiomics analyses using UpSet plots and feature extraction. Key findings were validated using immunoblots, redox measurements (NAD+/NADH ratio), imaging and senescence-associated molecular phenotype (SAMP) assays. Mechanistic studies included mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) to increase redox ratio and MitoTempo as a mitochondrial free radical scavenger. RESULTS: Multiomics analyses revealed enrichment in mitochondrial oxidative function, protein synthesis and senescence pathways consistent with the known effects of hypoxia-inducible factor 1α (HIF1α) during normoxia. Across preclinical and clinical models, HIF1α targets (n = 32 genes) and signalling genes (n > 100 genes) (n = 3 ATACseq, n = 65 phosphoproteomics, n = 10 acetylomics, n = 6 C2C12 proteomics, n = 106 C2C12 RNAseq, n = 64 hiPSC RNAseq, n = 30 hiPSC proteomics, n = 3 mouse proteomics, n = 25 mouse RNAseq, n = 8 human RNAseq, n = 3 human proteomics) were increased. Stabilization of HIF1α (C2C12, 6hEtOH 0.24 ± 0.09; p = 0.043; mALD 0.32 ± 0.074; p = 0.005; data shown as mean difference ± standard error mean) was accompanied by enrichment in the early transient and late change clusters, -log(p-value) = 1.5-3.8, of the HIF1α signalling pathway. Redox ratio was reduced in ET myotubes (C2C12: 15512 ± 872.1, p < 0.001) and mALD muscle, with decreased expression of electron transport chain components (CI-V, p < 0.05) and Sirt3 (C2C12: 0.067 ± 0.023, p = 0.025; mALD: 0.41 ± 0.12, p = 0.013). Acetylation of mitochondrial proteins was increased in both models (C2C12: 107364 ± 4558, p = 0.03; mALD: 40036 ± 18 987, p = 0.049). Ethanol-induced SAMP was observed across models (P16: C2C12: 0.2845 ± 0.1145, p < 0.05; hiPSCm: 0.2591, p = 0.041). MitoLbNOX treatment reversed redox imbalance, HIF1α stabilization, global acetylation and myostatin expression (p < 0.05). CONCLUSIONS: An integrated multiomics approach, combined with experimental validation, identifies HIF1α stabilization and accelerated post-mitotic senescence as novel mechanisms of sarcopenia in ALD. These findings show the complex molecular interactions leading to mitochondrial dysfunction and progressive sarcopenia in ALD.

Sarcopenia↗