bims-mikwok 2026-06-07 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2026–06–07
57 papers selected by
Gavin McStay, Liverpool John Moores University

BVDV utilizes PGC-1α downregulation to remodel the mitochondrial metabolic microenvironment, enhancing viral replication and impairing host immunity.
Chlorogenic Acid Modulates PINK1-Parkin-Mediated Mitochondrial Quality Control in T-2 Toxin-Induced Thymic Immunotoxicity.
Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.
Niacin Ameliorates EHDPHP-Induced Oxidative Stress and Mitochondrial Dysfunction in H9C2 Cells.
Cyclase-associated protein 1 facilitates actin-dependent mitochondrial fission in podocytes associated with diabetic nephropathy.
[Research progress on the roles of mitochondrial fusion, fission, and mitophagy in burn wound healing].
Trifloxystrobin-triggered Drp1 hyperactivation biases mitophagy and imposes long-lasting SVCV susceptibility in teleost.
NR3C1/PRKACG-mediated impairment of mitochondrial quality control underlies stress-induced hypothalamic neuronal injury.
Tectochrysin Ameliorates Colitis-Associated Colon Cancer in Mice Via the Activation of Mitophagy in Intestinal Epithelial Cells.
Traditional Chinese medicine-derived monomers delay osteoarthritis progression by regulating mitochondrial homeostasis.
FOXA1 protects against PM2.5-induced chronic lung injury via MARCHF8-dependent mitophagy inhibition.
Cell-specific energy crisis in the ageing brain: Mitochondrial dynamics drives neuron-glia metabolic uncoupling and neurodegeneration.
Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.
PLD3-mediated Mitophagy Attenuates Neuronal Ferroptosis and Promotes Functional Recovery after Spinal Cord Injury.
The Multiple Roles and Targeting Strategies of LonP1 in the Occurrence and Development of Cancer.
TIA-1 promotes FUNDC1-mediated mitophagy to protect against stress-induced cellular senescence.
Microglial Activation Mediates Drp1-Dependent Mitochondrial Fission and Neuronal Apoptosis in a Lipopolysaccharide-Induced Model of Cognitive Dysfunction.
Anemoside B4 inhibits mitochondrial dysfunction-related mitophagy in asthma by regulating KAT2B/IRF3 axis.
Nutritional redox reprogramming in cardiometabolic diseases: alpha-lipoic acid, urolithin A, and ergothioneine as modulators of the ferroptosis-mitophagy axis and mitochondrial metabolic remodeling.
AMPK/ULK1 enhances mitophagy and steroidogenesis in duck Granulosa cells under heat exposure.
Role of homocysteine in renal tubular epithelial-mesenchymal transition: N-homocysteinylation of β-catenin impairs FUNDC1-dependent autophagy and mitochondrial quality control.
USP33 alleviates FIS1-dependent mitochondrial fission and cardiac microvascular injury in diabetic cardiomyopathy via deubiquitinating and stabilizing ATG7.
DL-3-n-Butylphthalide Protects Against PrP106 -126-Induced Neurotoxicity Through NRF2 Signaling and OPA1/DRP1-Mediated Mitochondrial Dynamics.
Mitophagy in Pulmonary Fibrosis: Molecular Interactions, Hypoxia Interactions, and Therapeutic Strategies.
mTORC1-mediated inhibition of AMBRA1/PINK1/Parkin-dependent mitophagy contributes to renal podocyte injury in trichloroethylene-sensitized mice.
Altered mitochondrial functionality in metabolic disorders: insights from Drosophila studies.
Unmasking the apoptotic potential of DHODH inhibition through targeting adaptive mitophagy.
OTULIN protects hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31.
Regulation of mitochondrial protein translocases.
Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.
Wavelength-Dependent Photobiomodulation Regulates Macrophage Polarization via Mitochondrial Dynamics and Metabolic Reprogramming.
Mitochondrial dynamics in environmental neurotoxicity: beyond oxidative stress toward spatial and functional reorganization.
MMP7-Triggered mitophagy by regulating parkin-mediated ubiquitination of VDAC1 confers anoikis resistance in the epithelium of hyperplastic prostate.
Mitophagy in inflammatory bowel disease: regulatory mechanisms and therapeutic potential.
FTO Deficiency Inhibits Vascular Endothelial Cell Apoptosis and Improved Mitophagy in Obesity-Related Hypertension by Enhancing NDRG1 m6A Methylation.
Redox signals and oxidative stress in the control of mitochondrial protein import.
Redox imbalance and mitochondrial dysfunction in gestational diabetes mellitus: Implications for maternal health, placental function, and offspring metabolic programming.
SESN2 Drives Osteoarthritis Progression by Inducing MFN2-Dependent Mitochondrial Hyperfusion in Rats.
Chikusetsu saponin IVa mitigates septic cardiac injury by targeting DRP1 to suppress mitochondrial damage and NLRP3 inflammasome activation.
Heart failure and mitochondrial dynamics: Role of intracellular angiotensin and emerging therapeutics.
[Corrigendum] Electroacupuncture at GV20‑GB7 regulates mitophagy to protect against neurological deficits following intracerebral hemorrhage via inhibition of apoptosis.
Codonopsis pilosula as the sovereign herb in Shenling Baizhu formula ameliorates DSS-induced ulcerative colitis via spermidine-AMPK-mediated mitophagy to inhibit the cGAS-STING inflammatory axis.
Targeting the SARM1-cADPR-Ca2+ pathway attenuates mitochondrial fragmentation and osteoarthritis progression.
Provoking disulfidptosis-enhanced mitophagy by manganese-based nanoplatform via regulating cellular energy supply and redox homeostasis.
High Uric Acid Promotes Stem Leydig Cell Senescence by CCDC90B Mediates Mitochondrial Quality Control Imbalance.
Consequences of defective mitochondrial protein import: From targeting signals to pathology.
MFF Promotes Aggressive Phenotypes and Immunosuppression in Lung Adenocarcinoma via Mitochondrial Dysregulation.
Hyperoside protects against poly-GR-mediated neurodegeneration via regulation of mitochondrial fission and oxidative stress in C9orf72-associated ALS.
AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.
Evolving insights into mitochondrial presence in RBC in sickle cell disease: Red blood cell and reticulocyte pathophysiology, therapeutic strategies, and future directions.
Hydramethylnon-induced pulmonary toxicity associated with necroptosis signaling and mitochondrial dysfunction in human bronchial epithelial cells.
CHK1 activates mitophagy to attenuate cardiac aging via inhibiting AHSA1-ubiquitination.
From mitochondrial zonation to immune dysregulation: a mechanistic axis in diabetic cardiomyopathy.
Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.
M2 microglia-derived migrasome-enriched extracellular vesicles restore mitochondrial homeostasis to orchestrate neurovascular unit recovery after ischemic stroke.
Dietary phytoestrogen ameliorates ovarian toxicant-induced neurotoxicity: mechanistic and metabolic insights.
Activity-regulated circSamm50 modulates mitochondrial dynamics and spine structural plasticity.

Front Vet Sci. 2026 ;13 1799048

BVDV utilizes PGC-1α downregulation to remodel the mitochondrial metabolic microenvironment, enhancing viral replication and impairing host immunity.

Hongming Zhou, Yixing Zhao, Yuxin Kong, Jiying Yin, Ning He, Qi Wang, Jiayin Liu, Tongbo Zhou, Yu Han, Shouyi Dong, Yaru Zhao, Naichao Diao, Kun Shi, Rui Du.

   Introduction: Bovine viral diarrhea virus (BVDV) is a major pathogen affecting global livestock production, and virus-induced mitochondrial remodeling is closely associated with viral replication. However, the role of PGC-1α-mediated mitochondrial quality control in cytopathic BVDV strain NADL infection remains unclear.
Methods: MDBK cells were infected with CP BVDV(NADL) to establish an in vitro infection model. Mitochondrial morphology, function, mitophagy levels, and the expression of related proteins were examined using transmission electron microscopy, fluorescence staining, confocal microscopy, Western blotting, and the pADV-CMV-FH-cox8-EGFP-mCherry vector dual-fluorescence system. PGC-1α expression was manipulated by plasmid-mediated overexpression or shRNA-mediated knockdown.Viral replication was quantified by qRT-PCR, and IFN-β secretion was assessed by ELISA.
Results: CP BVDV(NADL) infection caused mitochondrial structural damage and dysfunction, accompanied by persistent downregulation of PGC-1α and its downstream target TFAM. Meanwhile, Drp1 expression was increased, shifting mitochondrial dynamics toward excessive fission. CP BVDV(NADL) infection also markedly enhanced PINK1-mediated mitophagy. Functionally, PGC-1α overexpression restored mitochondrial homeostasis, inhibited PINK1-dependent mitophagy, reduced IFN-β expression, and ultimately suppressed CP BVDV(NADL) replication. Conversely, PGC-1α interference further promoted mitophagy and increased mPTP opening.
Discussion: These findings demonstrate for the first time that CP BVDV(NADL) promotes viral replication by manipulating PGC-1α-mediated mitochondrial quality control. This mechanism reveals a novel metabolic strategy used by BVDV and provides potential therapeutic targets for controlling CP BVDV(NADL) infection.

Keywords:  BVDV; PGC-1α; mitochondrial biogenesis; mitochondrial quality control; viral replication

DOI:  https://doi.org/10.3389/fvets.2026.1799048
J Agric Food Chem. 2026 Jun 04.

Chlorogenic Acid Modulates PINK1-Parkin-Mediated Mitochondrial Quality Control in T-2 Toxin-Induced Thymic Immunotoxicity.

Dongguang Guo, Mingyan Chen, Ruiyan Niu, Yanfang Zhang, Zilong Sun.

  T-2 toxin (T-2), a potent immunotoxic trichothecene, induces severe thymic injury and immune dysfunction. Building on our identification of the ROS-NF-κB-NLRP3 axis, mitochondrial involvement remains poorly understood. Using murine and thymic epithelial cell models, we show that T-2 induces mitochondrial damage, activating PINK1-Parkin-mediated mitophagy that is adaptive but insufficient to maintain mitochondrial homeostasis. Inhibition of mitophagy by 3-methyladenine or Parkin silencing further compromised mitochondrial membrane potential by ∼34% and ∼22% versus T-2, respectively, accompanied by elevated intracellular ROS levels. Chlorogenic acid (CGA) ameliorated thymic atrophy, as evidenced by a ∼62% increase in thymus index versus T-2, enhanced PINK1-Parkin mitophagy, and alleviated oxidative, inflammatory, and apoptotic damage. Mechanistically, CGA modulated the KEAP1/SIRT1/AMPKα1 network, linking redox regulation to mitochondrial quality control, and its protective effects were largely abolished by PINK1 knockdown. Collectively, these findings establish insufficient mitophagy as a key driver of T-2 immunotoxicity and support CGA as a mitochondria-targeted dietary modulator.

Keywords:  PINK1–Parkin pathway; T-2 toxin; chlorogenic acid (CGA); mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.1021/acs.jafc.6c01391
Cell Death Dis. 2026 Jun 05.

Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.

Daniel Lagos, Pamela R de Santiago, Nicolás Pérez-Bravo, Benjamín Cartes-Saavedra, Josefa Vial-Brizzi, Diego Troncoso-Chandía, Oliver Podmanicky, Rita Horvath, Verónica Eisner.

Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2 A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants, we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analyzed mitochondrial morphology and dynamics by live-cell confocal microscopy and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and oxidative phosphorylation complex subunits. MFN2 mutations impaired mitochondrial fusion and displayed distinct effects on fission and cellular metabolism. L248H-expressing cells showed hyper-elongated mitochondria, impaired fission, and increased OCR, while M376V cells exhibited fragmentation, enhanced fission, and elevated ECAR. These effects correlated with differential Drp1 phosphorylation. Our findings demonstrate that MFN2 mutants differentially influence fission and metabolism, highlighting the need to consider these effects in therapies aimed at modulating mitochondrial dynamics.

DOI: https://doi.org/10.1038/s41419-026-08838-3
J Biochem Mol Toxicol. 2026 Jun;40(6): e70946

Niacin Ameliorates EHDPHP-Induced Oxidative Stress and Mitochondrial Dysfunction in H9C2 Cells.

Lizhi Dai, Jingxuan Wang, Jia Liu, Zheyuan Cao, Yuhao Zhang, Youchong Li, Tong Yu, Jianhua Xiao.

  2-Ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant frequently detected in environmental matrices and poses potential health risks. However, its cardiotoxic effects on mammalian cardiomyocytes and the underlying molecular mechanisms remain largely unclear. Niacin (NIA), an essential water-soluble vitamin, exhibits potent antioxidant, anti-inflammatory, and mitochondrial-protective activities. In this study, we investigated EHDPHP-induced toxicity in H9C2 cardiomyocytes and the protective effects of NIA. Cells were exposed to 100 μM EHDPHP alone or in combination with 400, 600, and 800 μM NIA. EHDPHP exposure significantly reduced cell viability, disrupted the balance between pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-18) and the anti-inflammatory cytokine IL-10, and induced oxidative stress, as evidenced by elevated ROS, MitoSOX, and MDA levels alongside decreased activities of antioxidant enzymes (SOD, GSH, GSH-Px, and CAT). Additionally, EHDPHP disturbed mitochondrial dynamics by promoting fission and inhibiting fusion, impaired mitochondrial biogenesis via downregulation of AMPK and PGC-1α, triggered excessive mitophagy through PINK1, PRKN, and LC3 upregulation, and activated pyroptosis via GSDMD, NLRP3, and Caspase-1. Bioinformatics analyses confirmed the interconnected regulatory network among mitochondrial dynamics, mitophagy, pyroptosis, and inflammatory signaling in EHDPHP-induced cardiomyocyte injury. Notably, NIA intervention dose-dependently mitigated these detrimental effects, restoring cell viability, alleviating inflammation and oxidative stress, rebalancing mitochondrial fusion and fission, rescuing biogenesis, normalizing mitophagy, and inhibiting pyroptosis. These findings reveal a pathological cascade through which EHDPHP induces cardiomyocyte injury and demonstrate that NIA confers cardioprotection by targeting multiple pathological pathways. This study provides novel mechanistic insights into EHDPHP-induced cardiotoxicity and highlights NIA as a promising nutritional intervention for reducing cardiovascular risks associated with environmental pollutants.

Keywords:  2‐ethylhexyl diphenyl phosphate (EHDPHP); H9C2 cardiomyocytes; Niacin (NIA); mitochondrial function; mitophagy; pyroptosis

DOI:  https://doi.org/10.1002/jbt.70946
Biochim Biophys Acta Mol Cell Res. 2026 Jun 01. pii: S0167-4889(26)00064-9. [Epub ahead of print]1873(6): 120166

Cyclase-associated protein 1 facilitates actin-dependent mitochondrial fission in podocytes associated with diabetic nephropathy.

Huimin Ma, Shuang Yao, Zihan Wang, Xinying Yu, Zongda Li, Rui Zhang, Haihai Liang, Jundong Jiao.

  Aberrant mitochondrial dynamics in podocytes are closely associated with the progression of diabetic nephropathy (DN); however, the underlying mechanisms remain incompletely understood. Recent research has demonstrated that cyclase-associated protein 1 (CAP1), an actin-binding protein, mediates mitochondrial fission. Therefore, we aimed to explore the regulatory role and mechanisms of CAP1 in high glucose (HG)-induced mitochondrial dysfunction in podocytes. CAP1 knockout reduced the severity of glomerular injuries and curtailed mitochondrial fission in podocytes in streptozotocin (STZ)-induced DN models. Subsequently, we observed that HG levels induced the mitochondrial translocation of CAP1 in podocytes, and CAP1 inhibition mitigated excessive mitochondrial fission. Mechanistically, our findings demonstrate that CAP1 facilitates HG-induced mitochondrial fission in podocytes by modulating actin reorganization. Furthermore, we present evidence that CAP1 interacts with Cofilin1, and this interaction plays a role in enhancing HG-induced mitochondrial fission in podocytes. This study elucidates the critical role of CAP1 in facilitating HG-induced mitochondrial fission in podocytes by regulating actin dynamics. These findings offer novel insights for the prevention and treatment of DN.

Keywords:  Actin; CAP1; Diabetic nephropathy; Mitochondrial fission; Podocyte

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120166
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2026 Jun 01. 1-8

[Research progress on the roles of mitochondrial fusion, fission, and mitophagy in burn wound healing].

Zehao Li, Weixue Jin, Songxue Guo.

  Mitochondria, known as the "energy factory" of cells, play a critical role in burn wound healing owing to their structural and functional stability. Following burn injury, mitochondrial damage exacerbates inflammatory responses, triggers endogenous apoptotic pathways, and reduces ATP synthesis, thereby delaying tissue repair. The dynamic balance between mitochondrial fusion and fission, together with mitophagy, is a key regulatory mechanism that maintains mitochondrial structural integrity and functional stability. Moderate mitochondrial fission promotes wound healing, whereas excessive fission induces overproduction of reactive oxygen species and inflammatory cytokines, which is detrimental to repair. Mitochondrial fusion may confer benefits to wound healing, and mitophagy alleviates apoptosis and oxidative stress, thereby regulating multiple stages of burn wound healing. This review focuses on the maintenance of the mitochondrial fusion-fission balance and mitophagy, elaborates their specific roles in burn wound repair, and discusses the clinical prospects of targeting these mechanisms for the prevention and treatment of post-burn injuries.

Keywords:  Burn wound; Mitochondrial fission; Mitochondrial fusion; Mitophagy; Review

DOI:  https://doi.org/10.3724/zdxbyxb-2026-0134
J Virol. 2026 Jun 01. e0044526

Trifloxystrobin-triggered Drp1 hyperactivation biases mitophagy and imposes long-lasting SVCV susceptibility in teleost.

Huan Wang, Yang Hu, Lei Liu, Jiong Chen.

  Environmental pollutants are increasingly recognized as disease modifiers, reshaping host homeostasis and shifting host-pathogen dynamics toward higher infection risk in aquatic ecosystems. Here, we show that the widely used strobilurin fungicide trifloxystrobin (TFS) persistently erodes antiviral competence in fish and increases susceptibility to spring viremia of carp virus (SVCV) by driving dynamin-related protein 1 (Drp1)-mediated excessive mitophagy and sustained mitochondrial dysfunction. Using epithelioma papulosum cyprini (EPC) cells and zebrafish as complementary models, we find that environmentally plausible TFS exposures (2.5-25 μg/L) elevate SVCV permissiveness; notably, this phenotype resolves incompletely after chemical withdrawal. Transcriptomics revealed a dose-concordant shift toward stress/innate immune signaling and mitophagy programs, alongside broad repression of proliferative and DNA-repair pathways. Consistently, TFS induces persistent mitochondrial membrane depolarization, promotes fragmentation and ultrastructural deterioration, and increases mitochondria-lysosome coupling. Mechanistically, TFS elevates Drp1 abundance and Ser616 phosphorylation, promotes Drp1 recruitment to mitochondria, and sustains microtubule-associated protein 1 light chain 3B (LC3B)/lysosomal-associated membrane protein 2 (LAMP2) engagement, accompanied by persistent induction of core autophagy regulators (gabarap, atg5, wipi1, and ambra1) across extended recovery windows. In vivo, prolonged TFS exposure similarly yields durable enhancement of SVCV susceptibility even after long recovery periods, indicating incomplete restoration of host resistance. Together, these findings link a major agricultural fungicide to persistent Drp1-driven mitophagy overactivation and identify long-term antiviral resistance as an ecologically relevant endpoint for pesticide risk assessment and aquatic disease forecasting.IMPORTANCEViral diseases pose a significant challenge to sustainable aquaculture, and effective antiviral interventions remain limited. In this study, we reveal that trifloxystrobin, a widely used fungicide, induces mitochondrial dysfunction and Drp1-mediated excessive mitophagy, leading to long-term suppression of antiviral immune responses in fish. Importantly, this work identifies mitochondrial dynamics as a key determinant of viral susceptibility and demonstrates how environmental pollutants can reshape host-pathogen interactions. By linking mitophagy and Drp1 activation to increased spring viremia of carp virus susceptibility, our findings provide a novel perspective on how pollutants may exacerbate viral infections in aquaculture species. This work underscores the urgent need for ecosystem-based antiviral strategies and offers a mechanistic framework for assessing ecological risks posed by common agricultural chemicals, thereby informing environmental and disease management in aquaculture.

Keywords:  SVCV; antiviral; mitochondrial dynamics; mitophagy; strobilurin fungicides; virus susceptibility

DOI:  https://doi.org/10.1128/jvi.00445-26
Commun Biol. 2026 Jun 04.

NR3C1/PRKACG-mediated impairment of mitochondrial quality control underlies stress-induced hypothalamic neuronal injury.

Guowei Zhang, Jingze Cong, Xiaowei Feng, Hongjian Xin, Weihao Zhu, Rui Shi, Chenyu Li, Yang Wang, Rufei Ma, Yingmin Li, Bin Cong, Weibo Shi.

The hypothalamus integrates autonomic, endocrine, and behavioral responses to stress, and stress-induced hypothalamic neuronal injury is implicated in various diseases. However, the underlying molecular mechanisms remain unclear. Mitochondria, as stress-sensitive organelles, play a critical role in cellular injury through structural and functional alterations. Here, we investigate how stress triggers mitochondrial quality control (MQC) dysfunction via glucocorticoid receptor (NR3C1) signaling, contributing to hypothalamic neuronal injury. Using acute and chronic stress rat models, we demonstrate that stress induces hypothalamic neuronal damage. Transmission electron microscopy and WB analysis reveal that stress promotes excessive mitochondrial fission while suppressing fusion, disrupting mitochondrial dynamics. At the cellular level, ChIP-Seq and siRNA experiments confirm that glucocorticoids (GCs) downregulate PRKACG (protein kinase A catalytic subunit gamma) expression via NR3C1-mediated transcriptional repression, reducing DRP1 (dynamin-related protein 1) phosphorylation at Ser637 and leading to aberrant mitochondrial fission. Furthermore, acute and chronic stress differentially activate mitophagy pathways, resulting in mitochondrial depletion. Intriguingly, neuronal death shifts from apoptosis to necroptosis under prolonged stress. In conclusion, our findings establish that NR3C1/PRKACG-mediated MQC dysfunction is a key mechanism in stress-induced hypothalamic neuronal injury. This study not only elucidates how GCs disrupt MQC but also advances our understanding of mitochondrial dysregulation in stress-related neuronal damage, providing a foundation for future mechanistic and therapeutic investigations.

DOI: https://doi.org/10.1038/s42003-026-10284-y
Mol Nutr Food Res. 2026 Jun;70(11): e70524

Tectochrysin Ameliorates Colitis-Associated Colon Cancer in Mice Via the Activation of Mitophagy in Intestinal Epithelial Cells.

Jikai He, Yuanmei Lou, Qichen Huang, Jinliang Dong, Qifeng Yu.

  Tectochrysin (TEC), a natural flavonoid, has shown efficacy in ameliorating chronic colitis. However, its therapeutic potential in colitis-associated colon cancer (CAC) remains unclear. This study aimed to investigate the interventional effects of TEC on an AOM/DSS-induced mouse CAC model and elucidate its underlying molecular mechanisms. The CAC mice model was established by induction with AOM/DSS. Mice were treated with TEC and/or the Drp1 inhibitor Mdivi-1. Western blot, qRT-PCR, transmission electron microscopy, immunofluorescence, and luciferase reporter assays were employed to assess mitophagy activation and related signaling pathways. TEC significantly alleviated CAC progression, as evidenced by reduced tumor burden, disease activity index, and weight loss. It activated mitophagy in intestinal epithelial cells (IECs) via the Pink1/Parkin pathway and reversed Mdivi-1-induced mitophagy inhibition. Tectochrysin ameliorates CAC by activating IEC mitophagy, highlighting its potential as a therapeutic agent for CAC.

Keywords:  Foxo3a; colitis‐associated colon cancer; intestinal epithelial cells; mitophagy; tectochrysin

DOI:  https://doi.org/10.1002/mnfr.70524
Front Cell Dev Biol. 2026 ;14 1845072

Traditional Chinese medicine-derived monomers delay osteoarthritis progression by regulating mitochondrial homeostasis.

Baohui Wang, Bo Dong.

  Osteoarthritis is a common degenerative disease characterized by the degeneration of articular cartilage, which also affects the synovium, subchondral bone, and the joint microenvironment. Currently, clinical treatment remains focused primarily on pain relief and symptom improvement, with a lack of disease-modifying strategies capable of effectively slowing disease progression. In recent years, the role of mitochondrial homeostasis imbalance in the pathogenesis and progression of osteoarthritis has gradually gained attention. Mitochondria not only participate in the energy supply of chondrocytes but are also closely associated with oxidative stress, mitochondrial dynamics, mitochondrial autophagy, apoptosis, cellular senescence, and extracellular matrix metabolism. In the osteoarthritis microenvironment, inflammatory stimuli, abnormal mechanical loading, and age-related stress disrupt mitochondrial function, leading to reactive oxygen species accumulation, membrane potential decline, and impaired energy metabolism, which in turn promote chondrocyte dysfunction and joint degeneration. A growing body of research indicates that single compounds derived from traditional Chinese medicine can exert protective effects by regulating mitochondrial homeostasis, thereby alleviating oxidative stress, improving energy metabolism, maintaining mitochondrial function, promoting moderate mitochondrial autophagy, and inhibiting chondrocyte apoptosis and senescence. Ultimately, these actions reduce inflammatory responses and matrix degradation, thereby delaying the progression of osteoarthritis. This article reviews the pathological role of mitochondrial homeostasis imbalance in osteoarthritis, summarizes recent research progress on TCM-derived monomers, and outlines current challenges and future directions.

Keywords:  TCM-derived monomers; chondrocytes; mitochondrial homeostasis; mitophagy; osteoarthritis

DOI:  https://doi.org/10.3389/fcell.2026.1845072
Environ Int. 2026 May 22. pii: S0160-4120(26)00283-7. [Epub ahead of print]213 110325

FOXA1 protects against PM2.5-induced chronic lung injury via MARCHF8-dependent mitophagy inhibition.

Xu Wu, Lingfeng Liu, Dafei Wei, Rongfang Tu, Fang Zhou, Jin Xu, Lin Chen, Sha Liu.

  The function and mechanism of the E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8) in fine particulate matter (PM2.5)-induced lung injury remain unknown. The effect of MARCHF8 overexpression on PM2.5-induced lung injury in mice was evaluated through lung pathology, apoptosis, and inflammation. The function of MARCHF8 was studied using HBE135-E6E7 and BEAS-2B cells stimulated by PM2.5. Mitochondrial autophagy was evaluated by the protein levels, mt-Keima ratio, MMP, mtROS, and LC3/PINK1/Parkin. The relationship of the FOXA1/MARCHF8/HK2 axis was detected by ChIP, Co-IP and cycloheximide. MARCHF8 expression decreased in PM2.5-exposed mouse lungs, HBE135-E6E7 and BEAS-2B cells, and COPD patients. Overexpressing MARCHF8 reduced PM2.5-induced cellular damage by inhibiting PINK1/Parkin-mediated mitophagy. Mechanistically, FOXA1 overexpression boosted MARCHF8 transcription. MARCHF8 promoted HK2 degradation by catalyzing k48-linked ubiquitination at the K763 site, leading to mitophagy inhibition by obstructing PINK1/Parkin recruitment. Furthermore, FOXA1 alleviated PM2.5-induced lung injury by inhibiting mitophagy via the MARCHF8/HK2/Parkin axis, and HK2 overexpression counteracted the protection against PM2.5-induced cytotoxicity provided by MARCHF8 or FOXA1. Meanwhile, the correlation between FOXA1, MARCHF8, and HK2 was validated in clinical samples of COPD patients. In conclusion, FOXA1 overexpression mitigates PM2.5-induced lung injury by suppressing mitophagy via the MARCHF8/HK2/Parkin axis, which may be a promising therapeutic strategy in the future.

Keywords:  FOXA1; HK2; MARCHF8; Mitophagy; PINK1/Parkin; PM2.5

DOI:  https://doi.org/10.1016/j.envint.2026.110325
Mech Ageing Dev. 2026 Jun 01. pii: S0047-6374(26)00058-8. [Epub ahead of print] 112206

Cell-specific energy crisis in the ageing brain: Mitochondrial dynamics drives neuron-glia metabolic uncoupling and neurodegeneration.

Kai Wang, Yongchao Liu, Haojia Zhang, Xiaomin Li, Rui Zhou, Wei Shao, Zijin Sun.

  Ageing is the primary risk factor for neurodegeneration and age-related cognitive decline, which is increasingly recognised as a systemic collapse of metabolic crosstalk between neurons and glial cells in the brain. This narrative review elucidates that mitochondrial dynamics - encompassing biogenesis, fusion, fission, and mitophagy - acts as the core regulatory mechanism governing this multicellular interaction network, and drives the cell-specific energy crisis that underpins pathological progression in the ageing brain. We delineate that senescent astrocytes disrupt the astrocyte-neuron lactate shuttle, oligodendrocytes develop ATP deficits triggering myelin breakdown, and microglia undergo maladaptive immunometabolism and metabolic reprogramming via excessive Drp1-mediated mitochondrial fission, which collectively initiates and amplifies chronic neuroinflammation and neurodegenerative damage. Crucially, we highlight intercellular mitochondrial transfer as a vital endogenous rescue mechanism, wherein glial cells donate functional mitochondria to stressed neurons to mitigate damage. Finally, we synthesise emerging therapeutic strategies targeting the glia-neuron mitochondrial social network, providing a holistic framework for restoring brain bioenergetic homeostasis and delaying age-related neurodegenerative progression.

Keywords:  Cell-Specific Energy Crisis; Immunometabolism; Intercellular Mitochondrial Transfer; Metabolic Reprogramming; Mitochondrial Dynamics

DOI:  https://doi.org/10.1016/j.mad.2026.112206
NPJ Aging. 2026 Jun 03.

Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.

Jiahui Yang, Jianfeng Li, Xintong Hou, Yifei Zheng, Zeyu Zhao, Ting Zhou, Tongwei Jing, Jiming Kong, Guohui Zhang, Ying Guo.

Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41514-026-00424-3
Mol Neurobiol. 2026 Jun 03. pii: 670. [Epub ahead of print]63(1):

PLD3-mediated Mitophagy Attenuates Neuronal Ferroptosis and Promotes Functional Recovery after Spinal Cord Injury.

Xintian Ding, Bin Dai, Jiafeng Peng, Kenan Sun, Shaoze Lan, Liu Yang, Canming Ye, Shenglong Pan, Chen Wang, Xinyu Liang, Ciren Lunzhu, Chun Chen, Yunliang Zhu, Jun Li.

  Ferroptosis is an important form of cell death following spinal cord injury (SCI), primarily caused by secondary microenvironmental alterations such as oxidative stress induced by local ischemia and hypoxia. Although Phospholipase D3 (PLD3) is known to contribute to neural homeostasis, its function in SCI and the associated mechanisms remain largely undefined. This study explores the role of PLD3 in the pathological process following SCI. In a mouse SCI model, proteomic analysis and biochemical assays revealed a marked reduction of PLD3 expression in injured spinal cord tissue, accompanied by elevated oxidative stress and ferroptosis markers. Adeno-associated virus-mediated overexpression of neuronal PLD3 significantly promoted spinal cord tissue repair and improved in vivo neurological function recovery. In an oxygen and glucose deprivation (OGD) model established using PC12 cells, PLD3 expression was significantly reduced, accompanied by mitochondrial dysfunction and increased oxidative stress and changes related to ferroptosis. PLD3 overexpression alleviated mitochondrial dysfunction, oxidative stress, and injury associated with ferroptosis in OGD-treated PC12 cells. Mechanistically, PLD3 overexpression was associated with activation of the PINK1/Parkin pathway, enhanced mitochondrial quality control responses related to mitophagy, and preservation of mitochondrial homeostasis. Complementary pharmacological experiments using Mdivi-1 and Cyclosporine A further supported an association between the protective effects of PLD3 overexpression, mitochondrial quality control, and injury related to ferroptosis. Collectively, these findings suggest that PLD3 overexpression helps maintain mitochondrial function and homeostasis in OGD-treated PC12 cells through mechanisms associated with PINK1/Parkin-related mitophagy. Together with the in vivo findings, these results provide new insight into secondary injury after SCI and support further investigation of PLD3 as a potential therapeutic target.

Keywords:  Ferroptosis; Mitophagy; Oxidative stress; Phospholipase D3; Spinal cord injury

DOI:  https://doi.org/10.1007/s12035-026-05986-7
Biofactors. 2026 May-Jun;52(3):52(3): e70121

The Multiple Roles and Targeting Strategies of LonP1 in the Occurrence and Development of Cancer.

Qun Zeng, Shitian Huang, Tingting Jiang.

  LonP1, a mitochondrial AAA+ protease, serves as a pivotal integrator of mitochondrial quality control (MQC) and metabolic reprogramming in cancer progression. Alternative splicing generates three functionally distinct isoforms: full-length ISO1 maintains mitochondrial homeostasis by degrading oxidized proteins and stabilizing mitochondrial transcription factor A (TFAM) for mtDNA integrity; truncated ISO2 (Δ42-105 AA) drives glycolytic reprogramming and epithelial-mesenchymal transition (EMT) by upregulating Snail/vimentin; and cytoplasmic ISO3 (Δ1-196 AA) lacks protease activity and is tumor-irrelevant. Tumor microenvironment (TME) cues (hypoxia, H. pylori infection, PFOA exposure, glutamine depletion) regulate LonP1 via Akt phosphorylation/Sirt3 deacetylation, coordinating MQC and metabolic adaptation to support cancer cell survival and metastasis. Functional data confirm its pro-tumor role: LonP1 upregulation enhances cervical cancer mitophagy and gastric cancer glycolysis, while knockdown induces mitochondrial dysfunction and apoptosis. This review summarizes current advances by (1) systematically integrating the isoform-specific functions of LonP1; (2) constructing a "LonP1-MQC-metabolism" regulatory network based on published evidence; and (3) proposing isoform-specific targeted strategies for precision oncology. These insights position LonP1 as a promising candidate for precision oncology, offering a cohesive understanding of mitochondrial regulation in cancer.

Keywords:  LonP1; cancer; isoform‐specific function; metabolic reprogramming; mitochondrial quality control

DOI:  https://doi.org/10.1002/biof.70121
Exp Mol Med. 2026 Jun 05.

TIA-1 promotes FUNDC1-mediated mitophagy to protect against stress-induced cellular senescence.

Seongho Cha, Myeongwoo Jung, Hyosun Tak, Seungyeon Ryu, Sukyoung Han, Dongwoo Chae, Jiyoon Kim, Seung Min Jeong, Wook Kim, Eun Kyung Lee.

Mitochondrial dysfunction, characterized by reduced mitophagy, excessive mitochondrial elongation, and elevated reactive oxygen species production, is a hallmark of cellular senescence. However, the molecular mechanisms linking impairment of redox balance to mitophagy suppression during senescence remain poorly understood. In this study, we identified TIA-1, an RNA-binding protein, as a positive regulator of FUNDC1 expression, a key receptor for ubiquitin-independent mitophagy. Sodium butyrate and ultraviolet-B irradiation triggered oxidative stress-associated senescence in HaCaT cells, leading to reduced TIA-1 expression, decreased FUNDC1 levels, impaired mitophagy flux, excessive mitochondrial elongation, and upregulation of senescence markers. Conversely, ectopic expression of TIA-1 restored FUNDC1 levels, enhanced mitophagy, improved mitochondrial function, and reduced senescence marker expression. Ribonucleoprotein immunoprecipitation assays confirmed that TIA-1 directly interacts with FUNDC1 mRNA, and subsequent analyses indicated that TIA-1 enhances FUNDC1 expression primarily through translational control. Together, these findings establish TIA-1 as a pivotal regulator of mitochondrial homeostasis during cellular stress, acting through FUNDC1 to sustain mitophagy and limit senescence. Targeting TIA-1 may offer new strategies to mitigate mitochondrial dysfunction and restore redox balance in aging and age-related diseases.

DOI: https://doi.org/10.1038/s12276-026-01752-w
Mol Neurobiol. 2026 Jun 06. pii: 680. [Epub ahead of print]63(1):

Microglial Activation Mediates Drp1-Dependent Mitochondrial Fission and Neuronal Apoptosis in a Lipopolysaccharide-Induced Model of Cognitive Dysfunction.

Meng-Jie Chen, Jia-Qi Ning, Jia-Xi Liu, Jian-Sheng Luo, Ru-Yu Yan, Yu-Xuan Yang, Xiang Li, Ling-Ling Ding.

  Neuroimmune dysregulation, characterized by microglial overactivation and imbalances in mitochondrial dynamics within the central nervous system represents a core pathological mechanism in postoperative cognitive dysfunction (POCD). This study investigated the neuroinflammation-mitochondrial interaction through the establishment of in vivo and in vitro models using lipopolysaccharide (LPS). Findings indicated that LPS-induced microglial overactivation was associated with marked upregulation of mitochondrial fission proteins, including phosphorylated Drp1 at Ser616, mitochondrial Drp1, and Fis1, along with downregulation of mitofusin-2. These alterations promoted mitochondrial fragmentation in hippocampal neurons, which subsequently led to mitochondrial membrane potential depolarization, adenosine triphosphate depletion, and excessive production of reactive oxygen species. This cascade further activated the intrinsic apoptotic pathway via Bax/Bcl-2 imbalance and caspase-9/3 activation. Conversely, administration of the Drp1 inhibitor Mdivi-1 reduced microglial activation, attenuated inflammatory cytokine levels, restored mitochondrial network integrity and function, inhibited neuronal apoptosis, and ameliorated LPS-induced spatial memory impairment in behavioral assays. These findings indicate that microglial activation-induced mitochondrial fission plays a pivotal role in inflammation-related cognitive impairment. Moreover, they highlight mitochondrial fission as a promising therapeutic target for intervention in POCD.

Keywords:  Cognitive impairment; Drp1; Mitochondrial fission; Neuroinflammation; Neuronal apoptosis

DOI:  https://doi.org/10.1007/s12035-026-05975-w
Mol Cell Biochem. 2026 Jun 02.

Anemoside B4 inhibits mitochondrial dysfunction-related mitophagy in asthma by regulating KAT2B/IRF3 axis.

Hao Tang, Ping Li, Mingxia Shang, Zhiping Zhou, Xing Yang, Bin Liu.

  Asthma is a classical inflammation-related disease, and its pathogenesis is closely associated with mitochondrial dysfunction and mitophagy. Although Anemoside B4 (AmB4) exhibits anti‑inflammatory properties in various diseases, its role in regulating mitochondrial dysfunction-related mitophagy in asthma remains unknown. In vivo and in vitro asthma models were constructed using house dust mite (HDM)-stimulated BALB/c mice and HDM-treated BEAS-2B cells. Hematoxylin and eosin and periodic acid-Schiff staining were used for the pathological examination of lung tissues. Mitophagy-related proteins were assessed by Western blotting and immunofluorescence. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were measured using JC-1 and DCFH‑DA assays, respectively. Mitochondria was observed by transmission electron microscopy. Cytokine concentrations were determined by ELISA. The mito‑Keima reporter was employed to directly quantify mitophagy and analyzed by flow cytometry. The effect of KAT2B on IRF3 protein stability was determined by cycloheximide chase assay. The ubiquitination of IRF3 was assessed by immunoprecipitation. Intermolecular interactions were analyzed using co-immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays. The results illuminated AmB4 alleviated asthma by downregulating KAT2B expression, thereby ameliorating mitochondrial dysfunction and suppressing mitophagy in vivo. Furthermore, AmB4 increased the MMP of BEAS-2B cells and reduced levels of ROS, LC3B, and Tomm20 via KAT2B inhibition. Mechanistically, KAT2B promoted the lysine acetylation of interferon regulatory factor 3 (IRF3) at K315, and IRF3 enhanced PTEN-induced putative kinase 1 (PINK1) expression by binding to its promoter. Additionally, AmB4 inhibited mitochondrial dysfunction-related mitophagy by targeting the KAT2B/IRF3/PINK1 axis, thereby alleviating asthma. Specifically, AmB4 suppressed IRF3-mediated PINK1 transcription by inhibiting KAT2B-dependent acetylation of IRF3 at K315, thereby ameliorating mitochondrial dysfunction and suppressing mitophagy, which ultimately improved asthma symptoms.

Keywords:  Anemoside B4; Asthma; IRF3; KAT2B; mitophagy

DOI:  https://doi.org/10.1007/s11010-026-05585-z
Front Nutr. 2026 ;13 1819082

Nutritional redox reprogramming in cardiometabolic diseases: alpha-lipoic acid, urolithin A, and ergothioneine as modulators of the ferroptosis-mitophagy axis and mitochondrial metabolic remodeling.

Wanzhou Yang, Weixiong Jian.

  Cardiometabolic disorders, encompassing atherosclerosis, myocardial ischemia, and myocardial infarction, persist as predominant contributors to morbidity and mortality on a global scale. An expanding corpus of research delineates redox imbalance, ferroptosis, compromised mitophagy, and mitochondrial metabolic dysfunction as pivotal determinants of cardiovascular pathophysiology. The paradigm of nutritional redox reprogramming has emerged as a potentially effective approach to modulate these interrelated pathways through the utilization of bioactive dietary compounds. This review emphasizes three novel nutraceutical modulators such as alpha-lipoic acid (ALA), urolithin A (UA), ergothioneine (EGT), and their respective functions in the regulation of ferroptosis, mitochondrial quality control, and cardiac bioenergetics. ALA exhibits multifaceted cardioprotective properties by diminishing oxidative stress, inhibiting lipid peroxidation, enhancing endothelial function, and restoring mitochondrial metabolism in the contexts of atherosclerosis and ischemic injury. UA, a metabolite derived from gut microbiota, primarily promotes mitophagy and mitochondrial biogenesis, thereby augmenting metabolic flexibility and enhancing resistance to ischemic stress. EGT, a thiol antioxidant derived from dietary sources and transported through the OCTN1 transporter, exhibits nascent potential in mitigating oxidative stress and maintaining mitochondrial homeostasis, although the mechanistic insights remain sparse. Collectively, these compounds signify promising candidates for the targeted modulation of redox status in cardiometabolic pathologies. Elucidating their common and unique molecular mechanisms may enhance the formulation of precision nutritional interventions aimed at preventing and mitigating the progression of cardiovascular diseases.

Keywords:  alpha-lipoic acid; atherosclerosis; cardiometabolic disorders; ergothioneine; ferroptosis; mitochondrial metabolism; myocardial ischemia; urolithin A

DOI:  https://doi.org/10.3389/fnut.2026.1819082
Poult Sci. 2026 May 25. pii: S0032-5791(26)00820-5. [Epub ahead of print]105(9): 107189

AMPK/ULK1 enhances mitophagy and steroidogenesis in duck Granulosa cells under heat exposure.

Xiaozhi Zhan, Pei Luo, Youtian Yang, Zhichao Deng, Cheng Zhang, Chen Yang, Yunmao Huang, Yunbo Tian, Wenjun Liu.

  Mitochondria play crucial roles in energy metabolism and steroidogenesis. Heat stress suppresses steroidogenesis in ovarian granulosa cells (GCs) and impairs poultry reproduction. Our previous study revealed that mitophagy protects duck GCs from acute heat exposure. Notably, numerous studies have demonstrated that the AMP-activated protein kinase/Unc-51-like kinase 1 (AMPK/ULK1) pathway is a key regulatory pathway for mitophagy. However, how AMPK coordinates mitophagy and steroidogenesis under heat stress remains unclear. This study aimed to elucidate the role of the AMPK/ULK1 axis in heat-induced mitophagy and steroidogenesis. Using a duck heat-treatment model and in vitro GC culture models, we combined Western blotting, targeted metabolomics, siRNA-mediated gene knockdown, and mitochondrial function assays to assess the impacts of the AMPK/ULK1 axis on mitophagy and steroidogenesis. We showed that heat treatment induced mitochondrial dysfunction, activated the AMPK/ULK1 pathway, triggered mitophagy, and suppressed steroidogenesis in duck ovarian tissue. In vitro, GCs exhibited similar mitochondrial impairment and AMPK/ULK1-dependent mitophagic activation under heat treatment. The LC-MS/MS analysis also confirmed elevated intracellular AMP levels in heat treatment GCs. Furthermore, activation of AMPK by 5'-aminoimidazole-4´-carboxamide ribonucleotide (AICAR) triggered mitophagy and enhanced steroidogenesis in GCs under heat treatment by upregulating the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 11A1 (CYP11A1), and cytochrome P450 19A1 (CYP19A1), whereas inhibition of AMPK by compound C exerted the opposite effect. Additionally, genetic knockdown of AMPK or ULK1 via siRNA reduced mitophagy and steroidogenesis under heat treatment. Taken together, the AMPK/ULK1 axis mediates heat-induced mitophagy and enhances GC steroidogenesis, positioning AMPK as a therapeutic target to improve heat-stressed poultry reproduction.

Keywords:  AMPK/ULK1; Granulosa cell; Heat exposure; Mitophagy; Steroidogenesis

DOI:  https://doi.org/10.1016/j.psj.2026.107189
Cell Signal. 2026 Jun 02. pii: S0898-6568(26)00283-4. [Epub ahead of print] 112630

Role of homocysteine in renal tubular epithelial-mesenchymal transition: N-homocysteinylation of β-catenin impairs FUNDC1-dependent autophagy and mitochondrial quality control.

Yanping Lei, Fang Guo, Hui Sun, Ji Huang, Yue Zhao.

  Given the nephrotoxicity of hyperhomocysteinemia and the key role of mitophagy in the homeostasis of kidney, this study investigated the β-catenin/FUNDC1/mitochondrial quality control axis to elucidate the mechanisms underlying homocysteine-induced renal tubular fibrosis. A mouse model of hyperhomocysteinemia was established via continuous supplementation of homocysteine. Western blot quantified key proteins associated with autophagy (FUNDC1, LC3, p62), fibrosis (fibronectin, α-SMA, Snail1), β-catenin signaling, and kidney injury (KIM-1). Immunostaining assessed renal spatial distribution of β-catenin, FUNDC1, α-SMA, and fibronectin, while transmission electron microscopy visualized mitochondrial ultrastructural changes. ChIP and dual-luciferase reporter assays verified the transcriptional target. Meanwhile, IP combined with mass spectrometry (MS), molecular modeling, and site-directed mutagenesis identified the modification site. β-catenin signaling inhibition by homocysteine resulted in diminished FUNDC1 expression within renal tubular epithelial cells, simultaneously suppressing autophagy and facilitating renal tubular fibrosis. β-catenin overexpression enhanced FUNDC1 expression, thereby rescuing homocysteine-suppressed autophagy and effectively mitigating renal tubular epithelial-mesenchymal transition (EMT). FUNDC1 overexpression mitigated homocysteine-induced cellular stress, further enhanced autophagy and mitochondrial quality control, and alleviated renal tubular EMT. Further, dual-luciferase reporter assays and ChIP confirmed FUNDC1 as a β-catenin transcriptional target. IP combined with MS, molecular modeling, and site-directed mutagenesis experiments revealed that homocysteine induced N-homocysteinylation of β-catenin at Lys49, which remodeled β-catenin's local structure to promote Ser45 phosphorylation and subsequent β-catenin degradation. Conclusively, homocysteine induces N-homocysteinylation of β-catenin at Lys49 to promote its degradation, thereby inhibiting β-catenin-mediated transcriptional activation of FUNDC1, disrupting autophagy and mitochondrial quality control, and ultimately inducing renal tubular EMT.

Keywords:  Autophagy; EMT; FUNDC1; Homocysteine; N-homocysteinylation; β-Catenin

DOI:  https://doi.org/10.1016/j.cellsig.2026.112630
Cell Death Dis. 2026 May 30.

USP33 alleviates FIS1-dependent mitochondrial fission and cardiac microvascular injury in diabetic cardiomyopathy via deubiquitinating and stabilizing ATG7.

Yuqiong Chen, Xiangyu Sun, Xinyan Li, Bo Guan, Xiaopei Yan, Chao Huang, Nannan Zhang, Wenjun Mao, Yuan Tian, Chao Chen, Yao Lu, Su Li.

Endothelial dysfunction plays a key role in the development of diabetic cardiomyopathy (DCM), but the underlying mechanisms of endothelial dysfunction remain to be elucidated. Recent studies have revealed that dysregulated mitochondrial dynamics contributes to the development of cardiac microvascular dysfunction. Fission-1 (FIS1), a key effector of mitochondrial fission, functions as an outer mitochondrial membrane adapter that recruits dynamin-related protein-1 (Drp1) from the cytosol to the outer mitochondrial membrane for activating mitochondrial fission. The present study screened a library targeting deubiquitinases, and identified the regulatory role of USP33 on FIS1-dependent mitochondrial fission. We found USP33 silencing elevated FIS1 protein expression and resulted in excessive mitochondrial fission in endothelial cells, which in turn impaired mitochondrial function and worsen endothelial and cardiovascular dysfunction in DCM. Mechanistically, USP33 interacted with FIS1 at the TPR2 domain and promoted FIS1 degradation via lysosomal degradation. Further studies revealed that USP33 stabilized autophagy-related 7 (ATG7) at protein level by blocking K63-linked ubiquitination of human ATG7 at K48 (mouse K44) site. This process led to lysosomal degradation of FIS1 via ATG7-mediated autophagy. In summary, our findings reveal that USP33 plays a critical role in endothelial dysfunction in DCM and demonstrate that ATG7-FIS1 pathway acts as one of the potential downstream mechanisms.

DOI: https://doi.org/10.1038/s41419-026-08930-8
CNS Neurosci Ther. 2026 Jun;32(6): e70948

DL-3-n-Butylphthalide Protects Against PrP106 -126-Induced Neurotoxicity Through NRF2 Signaling and OPA1/DRP1-Mediated Mitochondrial Dynamics.

Wei Wu, Xixi Zhang, Mingyue Jiang, Ning Ma.

   BACKGROUND: Prion diseases are fatal neurodegenerative diseases caused by misfolded prion protein. DL-3-n-butylphthalide (NBP), a synthetic agent derived from celery seeds, exhibits neuroprotective effects in multiple neurological disorders. However, its effects against prion peptide-induced neurotoxicity remain unclear.
METHODS: A PrP106-126-induced neurotoxicity model was established in N2a cells to evaluate the effects of NBP. Apoptosis, oxidative stress, mitochondrial function, mitochondrial dynamics, and respiratory chain integrity were assessed following NBP pretreatment. Mechanistic causality was examined using OPA1 knockdown, DRP1 overexpression, NRF2 inhibition, and NRF2 overexpression. Key findings were further validated in human iPSC-derived neurons.
RESULTS: NBP attenuated PrP106-126-induced neuronal apoptosis, decreasing cytochrome c release and caspase 3 cleavage. NBP also alleviated oxidative stress by lowering ROS and MDA levels, restoring T-AOC and SOD activity, and increasing NRF2/HO-1 signaling. In parallel, NBP preserved mitochondrial integrity and bioenergetics by maintaining MMP, ATP production, OCR, and mtDNA content, while sustaining respiratory chain complex expression and activity. NBP further normalized mitochondrial dynamics, restoring OPA1 levels and reducing DRP1 enrichment in mitochondrial fractions. Functionally, OPA1 knockdown, DRP1 overexpression, or NRF2 inhibition abolished NBP-mediated protection, whereas NRF2 overexpression recapitulated key protective effects and normalized OPA1/DRP1-related markers. Consistent protective trends were observed in human iPSC-derived neurons.
CONCLUSION: NBP mitigates PrP106-126-induced neurotoxicity by engaging NRF2-dependent antioxidant signaling and preserving mitochondrial homeostasis, with associated normalization of OPA1/DRP1-related mitochondrial dynamics. These findings support further evaluation of NBP in prion disease-relevant models.

Keywords:  DL‐3‐n‐butylphthalide; DRP1; NRF2; OPA1; mitochondrial dysfunction; oxidative stress; prion diseases

DOI:  https://doi.org/10.1002/cns.70948
Curr Med Chem. 2026 May 20.

Mitophagy in Pulmonary Fibrosis: Molecular Interactions, Hypoxia Interactions, and Therapeutic Strategies.

Xuelin Zhang, Lingjie Wang, Hongwang Yan, Yizhao Chen, Chunya He.

  Mitophagy plays a central role in the pathogenesis of Pulmonary Fibrosis (PF). Defective mitophagy leads to the accumulation of damaged mitochondria, resulting in bursts of mitochondrial Reactive Oxygen Species (mtROS), ferroptosis, and cellular senescence. These processes collectively promote aberrant fibroblast activation and excessive extracellular matrix deposition. This review systematically explored the molecular regulatory network of mitophagy in PF and its interactions with hypoxia-responsive pathways. These abnormalities create a vicious cycle of autophagy inhibition and fibrosis activation, which accelerates disease progression. Regarding therapeutic strategies, various small-molecule drugs and natural compounds have shown anti-fibrotic potential by activating mitophagy, alleviating oxidative stress, and delaying cellular senescence. Emerging technologies, such as gene therapy, nanocarriers, and combination therapies, are providing additional avenues for clinical translation. However, targeting mitophagy still faces challenges, including cell type specificity, dynamic conversion thresholds, and delivery efficiency. Future efforts will require integrating single-cell multi-omics and artificial intelligence approaches to develop spatiotemporally precise intervention systems for personalized, precision treatment of PF.

Keywords:  ECM.; Pulmonary fibrosis; lung tissue; mitochondria; mitophagy; reactive oxygen species

DOI:  https://doi.org/10.2174/0109298673451634260305040940
Toxicol Appl Pharmacol. 2026 Jun 01. pii: S0041-008X(26)00190-0. [Epub ahead of print]513 117894

mTORC1-mediated inhibition of AMBRA1/PINK1/Parkin-dependent mitophagy contributes to renal podocyte injury in trichloroethylene-sensitized mice.

Qirui Bai, Chen You, Zhuohui Qin, Qixing Zhu, Haibo Xie.

  Trichloroethylene (TCE) is extensively utilized within industrial settings. Certain individuals with occupational exposure may develop occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT), with renal injury being a predominant clinical manifestation among OMDT patients. Prior research has demonstrated that TCE-sensitized mice exhibit glomerular podocyte damage and activation of the mTOR signaling pathway, although the precise mechanisms remain unclear. In the present study, we employed Rapamycin, an mTORC1 inhibitor, to intervene in a TCE-sensitized mouse model. This was complemented by TCE-sensitized mice serum-induced mouse podocyte clone-5 (MPC5) cell model to elucidate the mechanism through which mTORC1 contributes to podocyte damage during TCE sensitization. The findings indicate that activation of mTORC1 results in the downregulation of autophagy/beclin-1 regulator-1 (AMBRA1) expression. Following intervention with Rapamycin, there was a significant restoration of AMBRA1 expression in mice, accompanied by increased mitophagy and decreased apoptosis levels. In vitro studies using cell culture models demonstrated that MPC5 cells exposed to serum from TCE-sensitized mice showed markedly reduced expression of PINK1 and Parkin proteins, along with suppressed mitophagy levels. Treatment with Rapamycin or si-AMBRA1 effectively enhanced cellular mitophagy and diminished apoptosis. This study elucidates that TCE sensitization activates the mTORC1 signaling pathway, leading to the downregulation of AMBRA1. The suppression of AMBRA1 impedes the PINK1/Parkin-dependent mitophagy pathway, hindering the timely clearance of damaged mitochondria in podocytes. Consequently, this results in the release of cytochrome C into the cytoplasm, which triggers podocyte apoptosis signaling, compromises the integrity of the glomerular filtration barrier, and ultimately leads to renal dysfunction.

Keywords:  AMBRA1; Apoptosis; Mitophagy; OMDT; mTORC1

DOI:  https://doi.org/10.1016/j.taap.2026.117894
Front Endocrinol (Lausanne). 2026 ;17 1817121

Altered mitochondrial functionality in metabolic disorders: insights from Drosophila studies.

Yunlin Zeng, Yang Yang, Yuao Zhu, Peixin Xu, Chakin Cheong, Yong Juan Zhao, Gyeong Hun Baeg.

  The pathophysiological association between obesity and type 2 diabetes (T2D) increasingly highlights the central role of mitochondrial dysfunction. As critical signaling hubs orchestrating metabolism, mitochondria are pivotal in maintaining metabolic homeostasis. Imbalances in mitochondrial quality control mechanisms lead to an accumulation of damaged mitochondria with abnormal dynamics and functions, exacerbating the progression of obesity, insulin resistance, and T2D. Although therapeutic interventions for obesity and T2D have shown promise, they remain insufficient for achieving sustained remission from obesity and T2D on a global scale. Furthermore, existing rodent models often struggle to fully recapitulate human metabolic disorders due to species-specific metabolic differences and technical limitations. Drosophila melanogaster has emerged as a powerful model organism for deciphering mitochondrial-metabolism interactions due to numerous advantages, including easy genetic manipulation, low gene redundancy, rapid phenotype verification, and the unique opportunity to image live tissues in vivo. Drosophila models effectively recapitulate high-sugar- and high-fat-diet-induced mitochondrial fragmentation, adipose tissue expansion, and insulin resistance-like phenotypes. Furthermore, studies leveraging the genetic tractability of Drosophila have provided critical insights into how mitochondrial impairment contributes to systemic metabolic dysfunction. Here, we introduce recent advances in mitochondrial research regarding metabolic disorders and demonstrate how Drosophila serves as a useful in vivo model to dissect mitochondrial function. Future research should integrate multi-omics approaches and precision medicine strategies targeting mitochondrial metabolic remodeling to break the vicious cycle of obesity and T2D, while developing non-invasive intervention methods to advance translational medicine.

Keywords:  Drosophila melanogaster; mitochondrial dysfunction; mitochondrial quality control; mitophagy; obesity and type 2 diabetes

DOI:  https://doi.org/10.3389/fendo.2026.1817121
Front Cell Dev Biol. 2026 ;14 1817489

Unmasking the apoptotic potential of DHODH inhibition through targeting adaptive mitophagy.

Xiaowen Huang, Zichang Guo, Bowen Liu, Hongyun Tang.

  Targeting dihydroorotate dehydrogenase (DHODH) to restrict de novo pyrimidine synthesis is a promising anticancer strategy. However, the efficacy of DHODH inhibitors, such as brequinar (BQR), is often constrained by modest single-agent cytotoxicity, necessitating the exploration of combination therapies. Here, using mt-Keima-based mitophagy reporters and CRISPR/Cas9-mediated gene knockout models, we reveal a critical adaptive mechanism whereby BQR-induced mitochondrial reactive oxygen species (mtROS) trigger protective mitophagy. Crucially, we demonstrate that inhibiting this autophagy process synergistically enhances BQR's anti-tumor activity both in vitro and in vivo. This combination leads to enhanced mtROS accumulation and severe lipid peroxidation, ultimately triggering caspase-dependent apoptosis, while ferroptosis does not appear to be the dominant mechanism under these conditions. Our findings identify mitophagy as a key mechanism of resistance to DHODH inhibition and provide a strong rationale for a combinatorial strategy to enhance the therapeutic efficacy of this class of drugs.

Keywords:  ATG7; DHODH inhibition; apoptosis; chloroquine; mitophagy; mtROS

DOI:  https://doi.org/10.3389/fcell.2026.1817489
Cell Mol Biol Lett. 2026 May 30.

OTULIN protects hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31.

Li Huang, Qing Liu, Aimin Zhang, Yanhan Liu, Furong Huang, Juanmei Wang, Manting Tan, Duane Wang, Menghua Zhao, Xu Wu.

  The deubiquitinating enzyme OTULIN has been implicated in the development of lung injury, and regulating its expression may either exacerbate or alleviate pulmonary inflammatory damage. In this study, we aimed to investigate the role of deubiquitinating enzyme OTULIN in hyperoxia-induced lung injury and the underlying mechanisms involved. A bronchopulmonary dysplasia (BPD) model was established by exposing neonatal mice to a hyperoxic environment, and the effects of regulating OTULIN expression on mitochondrial homeostasis in pulmonary epithelial cells were further examined under hyperoxic conditions. In addition, we investigated the mechanisms through which OTULIN regulates mitochondrial-associated proteins and the ubiquitination mechanisms of differential mitochondrial protein OPA1. The results showed that hyperoxia induced significant lung injury in neonatal mice and was accompanied by upregulation of OTULIN expression. Additionally, hyperoxia disrupted mitochondrial homeostasis in neonatal mice lung tissue, as observed by a reduction in mitochondrial number and increased mitochondrial fusion and autophagy. After hyperoxia exposure, overexpression of OTULIN significantly reduced mitochondrial reactive oxygen species (ROS) levels in alveolar epithelial cells, maintained mitochondrial membrane potential, and promoted mitochondrial homeostasis. Mechanistically, OTULIN was found to directly interact with OPA1 and regulate its ubiquitination status. The E3 ubiquitin ligase RNF31 was identified as a key regulator of OPA1 stability, with knockdown of RNF31 reducing OPA1 levels. Moreover, OTULIN regulated the expression of both OPA1 and RNF31 and affected the stability of OPA1 and mitochondrial function through RNF31-dependent mechanisms. In vivo experiments further showed that knockdown of OTULIN aggravated hyperoxia-induced lung injury in neonatal mice, characterized by alveolar simplification, increased fibrosis, and further impairment of mitochondrial function, whereas overexpression of OTULIN alleviated these pathological changes. In conclusion, deubiquitinating enzyme OTULIN protected hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31. These findings provide new insights into the pathogenesis of BPD and highlight the therapeutic potential of targeting the OTULIN/RNF31-OPA1 axis.

Keywords:  Hyperoxia; Mitochondria; Neonatal lung injury; OPA1; OTULIN; Ubiquitination

DOI:  https://doi.org/10.1186/s11658-026-00946-4
Protein Sci. 2026 Jul;35(7): e70662

Regulation of mitochondrial protein translocases.

Lea Bertgen, Agnieszka Chacinska.

  Mitochondria are essential for cellular health, and their function is underlain by the plasticity of the mitochondrial proteome. Most mitochondrial proteins are nuclear encoded, synthesized in the cytosol, and require precise import into mitochondrial subcompartments to fulfill their proper functions. Multimeric mitochondrial translocases ensure accurate protein localization and membrane integration. Recent work has begun to reveal how translocase activity and composition are dynamically regulated within mammalian cells. This review discusses regulatory mechanisms, including phosphorylation and protein degradation, that emerge as important players in adjusting the capacity and/or selectivity of the mitochondrial translocase to metabolic demands. Particular emphasis will be placed on the TIM23 complex as an emerging regulator of the inner membrane and matrix proteome composition.

Keywords:  TIM23 complex; TOM complex; mitochondria; mitochondrial biogenesis; proteases; protein translocases; protein turnover

DOI:  https://doi.org/10.1002/pro.70662
bioRxiv. 2026 May 22. pii: 2026.05.20.726663. [Epub ahead of print]

Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.

Salma Sharmin, Jennifer A Kashatus, Sara J Adair, Emma Bakall Loewgren, Mohammad Fallahi-Sichani, Todd W Bauer, David F Kashatus.

Background: In RAS-mutant tumors, ERK phosphorylates the mitochondrial fission GTPase DRP1 to promote mitochondrial fission. DRP1 activity is tumor-promoting in pancreatic and other RAS-driven cancers, but its role in therapeutic resistance is unknown.
Methods: We developed a panel of patient-derived pancreatic cancer cell lines resistant to the MEK inhibitor trametinib. We used immunofluorescence imaging, in vitro growth assays and orthotopic xenografts to determine the role of DRP1 in trametinib resistance.
Results: We find that trametinib-resistant cells exhibit increased expression and phosphorylation of DRP1 compared to sensitive counterparts. Quantitative analysis of mitochondrial structure reveals that mitochondria in resistant cells are morphologically distinct and relatively smaller than sensitive cells treated with trametinib. Genetic and pharmacological inhibition of both c-Myc and CDK6 are sufficient to block DRP1 phosphorylation in resistant cells, suggesting that activation of a c-Myc-CDK6 signaling axis drives reactivation of mitochondrial fission in the absence of MAPK signaling. Importantly, deletion of DRP1 leads to either growth inhibition or re-sensitization to trametinib in resistant lines.
Conclusion: These findings suggest DRP1 contributes to drug resistance, and that inhibition of mitochondrial fission might be a promising therapeutic strategy to combat resistance to MAPK and RAS inhibitors.

DOI: https://doi.org/10.64898/2026.05.20.726663
Adv Sci (Weinh). 2026 Jun 02. e75920

Wavelength-Dependent Photobiomodulation Regulates Macrophage Polarization via Mitochondrial Dynamics and Metabolic Reprogramming.

Qiusheng Shi, Hao Jia, Jianfei Dong, Linhao Li, Jingqi Cao, Xun Chen, Zhenzhen Jia, Jing Na, Zhijie Yang, Xinyuan Chen, Yubo Fan, Shuhua Yue, Lisha Zheng.

  Photobiomodulation (PBM) provides a non-invasive means to regulate immune function, yet its clinical translation is hindered by a lack of mechanistic links between light parameters and biological outcomes. Here, we demonstrate that specific wavelengths act as metabolic switches that direct macrophage polarization through the selective engagement of distinct immunometabolic pathways. In both in vitro and in vivo wound healing models, 850-nm light enhances fatty acid oxidation and lipid droplet-mitochondria interactions, driving anti-inflammatory M2 polarization and accelerating tissue repair. Conversely, 625 nm light increases glycolytic flux and lactate production, promoting a pro-inflammatory M1 state that delays healing. We identify mitochondrial dynamics as the key interface: 850 and 625 nm light promote mitochondrial fusion and fission, respectively, to dictate metabolic routing. Causality was confirmed via metabolic interventions, which reversed wavelength-specific polarization outcomes. Together, these findings define photo-immunometabolism as a wavelength-dependent framework in which light regulates macrophage fate through coordinated control of mitochondrial dynamics and metabolism. This framework provides a mechanistic basis for precision, wavelength-tailored PBM therapies for wound repair and other immune-mediated inflammatory disorders.

Keywords:  fatty acid oxidation; glycolysis; macrophage polarization; mitochondrial dynamics; photobiomodulation; wound healing

DOI:  https://doi.org/10.1002/advs.75920
Arch Toxicol. 2026 Jun 04.

Mitochondrial dynamics in environmental neurotoxicity: beyond oxidative stress toward spatial and functional reorganization.

Xinyi Yu, Weiqi Lin, Wenqi Hu, Dingxin Long, Weichao Zhao.

  Environmental stressors are widely recognized as key drivers of neurotoxicity, yet their underlying mechanisms are still predominantly interpreted within a damage-centered framework focused on mitochondrial dysfunction, particularly oxidative stress and bioenergetic impairment.This perspective, primarily based on measurements of oxidative stress and bioenergetic impairment, cannot fully explain the spatial heterogeneity and selective vulnerability that define neuronal injury. Increasing evidence indicates that mitochondrial dynamics, including fission-fusion balance, intracellular transport, and quality control, function as an integrated regulatory system that actively organizes mitochondrial networks. Through the coordination of spatial distribution, functional renewal, and damage segregation, these processes shape how neurons respond to environmental challenges. Rather than serving as passive indicators of injury, mitochondrial dynamics determine whether cells maintain adaptive compensation or progress toward irreversible degeneration. In this review, we summarize how environmental stressors disrupt mitochondrial biology and propose mitochondrial dynamics as a central axis linking environmental exposure to neuronal fate. This perspective shifts the focus from static descriptions of dysfunction to dynamic regulation of mitochondrial networks and provides a conceptual framework for understanding heterogeneous neurotoxic outcomes while highlighting new opportunities for therapeutic intervention.

Keywords:  Environmental stressor; Mitochondrial dynamics; Mitochondrial transport; Neurotoxicity

DOI:  https://doi.org/10.1007/s00204-026-04451-7
Cell Death Dis. 2026 Jun 01.

MMP7-Triggered mitophagy by regulating parkin-mediated ubiquitination of VDAC1 confers anoikis resistance in the epithelium of hyperplastic prostate.

Yongying Zhou, Yan Li, Huan Liu, Junchao Zhang, Jizhang Qiu, Lu Du, Huan Lai, Ping Chen, Yuming Guo, Yongwen Luo, Michael E DiSanto, Xinhua Zhang.

Benign prostatic hyperplasia (BPH), prevalently in aging men, is characterized by aberrant cell death of prostate cells. Anoikis, a specific subtype of apoptosis, is triggered when cells detach from the extracellular matrix (ECM), in contrast, cells with anoikis resistance contribute to pathological processes such as unregulated cell proliferation and impaired cell death. However, the role of anoikis resistance in BPH pathogenesis remains poorly understood. In this study, an elevated anoikis resistance level was observed in BPH tissues compared to normal prostates. Furthermore, matrix metalloproteinase 7 (MMP7) was identified as a key regulator of anoikis resistance in hyperplastic prostatic epithelium. Under anoikis-inducing conditions, MMP7 promoted mitophagy via the PINK1-Parkin pathway, alleviated mitochondrial stress damage, and enhanced anoikis resistance in BPH-1 cells. Mechanistically, MMP7 interacted with VDAC1 and bound specifically to lysine residues K109 and K110, thereby inhibiting VDAC1 oligomerization and increasing the accumulation of VDAC1 monomers, which served as additional binding sites to Parkin-mediated polyubiquitination. Moreover, clinical data revealed that MMP7 expression levels correlated significantly with the International Prostate Symptom Score (IPSS) and nocturia frequency. Additionally, in vivo experiments demonstrated that inhibition of MMP7 suppressed mitophagy and markedly attenuated prostatic epithelial hyperplasia in a rat model BPH. Collectively, our findings clarify the functional role of the MMP7-VDAC1 axis in BPH pathogenesis and highlight its potential as a therapeutic target for BPH management.

DOI: https://doi.org/10.1038/s41419-026-08867-y
Front Cell Dev Biol. 2026 ;14 1804813

Mitophagy in inflammatory bowel disease: regulatory mechanisms and therapeutic potential.

Sixuan Chen, Jing Guan, Xia Pang, Xi Chen, Min Li, Huan Wang, Fei Mao.

  Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract driven by complex interactions among genetic susceptibility, barrier dysfunction, and immune dysregulation. Mitophagy, the selective autophagic clearance of damaged mitochondria, has emerged as a key regulator of intestinal homeostasis and immune balance. Impaired mitophagy compromises epithelial barrier integrity, amplifies inflammatory signaling, and promotes disease progression. This review summarizes the molecular mechanisms of mitophagy, examines its involvement in IBD pathogenesis across intestinal epithelial and immune cell compartments, and highlights mitophagy-modulating compounds that may inform the development of novel therapeutic strategies.

Keywords:  genetic susceptibility; immune cells; inflammatory bowel disease; intestinal barrier; mitophagy

DOI:  https://doi.org/10.3389/fcell.2026.1804813
Biochem Genet. 2026 Jun 04.

FTO Deficiency Inhibits Vascular Endothelial Cell Apoptosis and Improved Mitophagy in Obesity-Related Hypertension by Enhancing NDRG1 m6A Methylation.

Qinglei Gan, Na Yang.

  Vascular endothelial dysfunction contributes to obesity-related hypertension, yet its mechanisms remain unclear. This study examined the role of N6-methyladenosine (m6A) in this process using in vivo and in vitro models. C57BL/6J mice fed a high-fat diet (HFD) developed obesity-related hypertension, while oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs) simulated endothelial injury. Global m6A levels were assessed via dot blot, and m6A regulators were quantified by qPCR. Endothelial function was evaluated through viability (CCK-8), apoptosis (flow cytometry), and mitophagy (Western blot and immunofluorescence staining). Mechanistic studies included methylated RNA immunoprecipitation (MeRIP) and dual-luciferase assays. Results showed HFD reduced m6A levels but elevated Fto expression in mice, while ox-LDL decreased m6A levels and upregulated FTO in HAECs. FTO knockdown in HAECs enhanced viability and mitophagy while suppressing apoptosis under ox-LDL stress. Mechanistically, FTO silencing increased m6A methylation on NDRG1 mRNA, leading to its degradation via YTHDF2 recognition. NDRG1 overexpression reversed these effects, restoring apoptosis while reducing mitophagy and viability. These findings reveal that FTO depletion attenuates endothelial dysfunction in obesity-related hypertension by enhancing m6A-mediated suppression of NDRG1, highlighting the FTO/m6A/NDRG1/YTHDF2 axis as a therapeutic target for vascular protection.

Keywords:  FTO; Hypertension; NDRG1; Obesity; Vascular endothelial cell; m6A

DOI:  https://doi.org/10.1007/s10528-026-11410-5
Protein Sci. 2026 Jul;35(7): e70665

Redox signals and oxidative stress in the control of mitochondrial protein import.

Lidwina Hasberg, Viktoria Katharina Lauterbach, Torsten Ochsenreiter, Jan Riemer.

  Mitochondrial protein import is essential for organelle biogenesis and cellular homeostasis. It operates in an environment that is intrinsically shaped by redox chemistry. Mitochondria are major sources of reactive oxygen species (ROS), which arise as by-products of oxidative phosphorylation. Cells therefore maintain sophisticated ROS-handling systems, including compartmentalized antioxidant networks, to balance redox signaling with protection from oxidative stress. Increasing evidence indicates that these redox conditions directly influence mitochondrial protein import at multiple levels. In this review, we provide an overview of ROS production, ROS signaling, and oxidative stress in relation to mitochondrial protein import. We outline the major mitochondrial protein import pathways, and discuss how their activity is modulated by redox-dependent mechanisms. A particular focus is placed on the mitochondrial disulfide relay system of the intermembrane space, which directly couples protein import to redox chemistry through oxidative folding, and how it is influenced by the local redox environment. Collectively, we propose that mitochondrial protein import is partially governed by redox-dependent mechanisms, enabling integration of metabolic state, stress responses, and signaling pathways.

Keywords:  disulfide relay; mitochondrial protein import; oxidative stress; reactive oxygen species (ROS); redox signaling

DOI:  https://doi.org/10.1002/pro.70665
Free Radic Biol Med. 2026 Jun 04. pii: S0891-5849(26)00841-5. [Epub ahead of print]253 478-486

Redox imbalance and mitochondrial dysfunction in gestational diabetes mellitus: Implications for maternal health, placental function, and offspring metabolic programming.

Izabela Burzynska-Pedziwiatr, Lucyna A Wozniak, Malgorzata Bukowiecka-Matusiak.

  Mitochondrial dysfunction and redox imbalance are increasingly recognised as essential factors in the pathophysiology of gestational diabetes mellitus (GDM). Impaired oxidative phosphorylation in the placenta, increased production of reactive oxygen species (ROS), and insufficient antioxidant protection impair bioenergetics and affect maternal-foetal nutrient exchange. Such changes promote excessive foetal growth and metabolic programming while predisposing mothers to future type 2 diabetes. Current research indicates alterations in mitochondrial dynamics and mitophagy as additional risk factors for placental disease. The placenta is not only a passive recipient of maternal hyperglycaemia; it actively participates in metabolic signalling at the maternal-foetal interface. This structure identifies placental mitochondria as potential therapeutic targets. Preclinical studies on mitochondrial antioxidants (SS-31, MitoQ), uncoupling factors, and biogenesis-supporting substances have shown great potential in restoring mitochondrial integrity and reducing oxidative stress. However, there is still no clinical confirmation of their effectiveness during pregnancy. A comprehensive understanding of mitochondrial redox processes during gestational diabetes offers unique potential for improving pregnancy outcomes and may contribute to reducing the intergenerational inheritance of metabolic diseases.

Keywords:  Antioxidant defence; Foetal programming; Gestational diabetes; Mitochondria; Mitochondrial dynamics; Oxidative stress; Placenta; Redox signalling

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.337
Osteoarthritis Cartilage. 2026 Jun 01. pii: S1063-4584(26)00922-2. [Epub ahead of print]

SESN2 Drives Osteoarthritis Progression by Inducing MFN2-Dependent Mitochondrial Hyperfusion in Rats.

Yiwen Zhang, Zehang Zheng, Wenjie Hou, Chunran Pan, Kai Sun, Jiyun Li, Xiaofeng Deng, Xingru Shang, Jiawei Liu, Ruimin Chi, Xiaoxia Hao, Fengjin Guo, Tao Xu.

   OBJECTIVE: This study aimed to elucidate the role of SESN2 in the pathological process of osteoarthritis (OA), with a particular focus on its potential mechanism in regulating chondrocyte mitochondrial function.
DESIGN: In vitro and in vivo inflammatory models were established using SpragueDawley rats via IL-1β stimulation and surgical destabilization of the medial meniscus (DMM). siRNA, overexpression plasmids, and adeno-associated viruses were used to investigate the role of SESN2 in OA progression, and mechanistic studies were performed to clarify the underlying pathways and downstream targets.
RESULTS: SESN2 expression was significantly upregulated in the chondrocytes and cartilage tissues of OA rats. SESN2 overexpression exacerbated IL-1β-induced chondrocyte inflammation and DMM-induced cartilage damage (OARSI score, 2.000 [95% CI: 0.000 to 5.000]); conversely, SESN2 knockdown alleviated metabolic disorders and mitochondrial dysfunction in the matrix (Relative ATP content, 0.2639 [95% CI: 0.1068 to 0.4209]) and ameliorated cartilage degeneration in vivo (OARSI score, -2.000 [95% CI: -5.000 to -1.000]). Mechanistic studies revealed that SESN2 induced mitochondrial hyperfusion in chondrocytes (Mean branch length, 0.4821 [95% CI: 0.2707 to 0.6935]) and exacerbated mitochondrial dysfunction and inflammation via excessive mitochondrial fusion mediated by MFN2. Further investigation revealed that SESN2 upregulated MFN2 protein expression by promoting its dephosphorylation (Relative protein expression, 0.7693 [95% CI: 0.5392 to 0.9994]), thereby inducing mitochondrial hyperfusion.
CONCLUSIONS: SESN2 promotes chondrocyte mitochondrial dysfunction and the pathological progression of OA by regulating MFN2 dephosphorylation to induce mitochondrial hyperfusion, thereby providing a new potential target for intervention in OA.

Keywords:  Chondrocyte; MFN2; Mitochondrial hyperfusion; Post-traumatic OA; SESN2

DOI:  https://doi.org/10.1016/j.joca.2026.05.014
Life Sci. 2026 Jun 02. pii: S0024-3205(26)00318-8. [Epub ahead of print]401 124509

Chikusetsu saponin IVa mitigates septic cardiac injury by targeting DRP1 to suppress mitochondrial damage and NLRP3 inflammasome activation.

Wen Tian, Zhi-Yong Yu, Zhuo Li, Xu-Yang Zheng, Yi-Di Ding, Deng-Hui Yu, Fei Hu, Meng-Yuan Li, Xiao-Fei Yang, Huan-Jun Shen, Jian-Qi Lian.

   AIMS: Sepsis-induced myocardial injury represents a serious complication with limited treatment options. Chikusetsu saponin IVa (CHS), a triterpenoid saponin derived from Rhizoma Panacis japonica, exhibits potent anti-inflammatory and cardioprotective properties, positioning it as a promising candidate.
MATERIALS AND METHODS: To elucidate the therapeutic potential and mechanism of CHS in septic cardiac dysfunction, the effects of CHS administration on lipopolysaccharide (LPS, 40 mg/kg, i.p.) and cecal ligation and puncture (CLP)-induced septic murine models were evaluated through echocardiography and histological analyses. Network pharmacology and limited proteolysis-mass spectrometry (LiP-MS) were exploited to dissect the specific mechanisms and targets of CHS. Immunofluorescence, co-immunoprecipitation, and electron microscopy were performed to validate the effects of CHS on mitochondrial integrity, inflammasome assembly, and pyroptotic injury in LPS-ATP-stimulated cardiomyocytes.
KEY FINDINGS: CHS administration significantly mitigated LPS-induced cardiac injury and dysfunction of mice. CHS effectively inhibited NLRP3 upregulation, Caspase-1 activation, GSDMD cleavage, and subsequent pyroptosis both in vivo and in vitro. LiP-MS and microscale thermophoresis identified DRP1 as the direct binding protein of CHS. Cellular thermal shift assay and drug affinity responsive target stability assays further indicated that CHS improved the proteolytic and thermal stability of DRP1. CHS or DRP1 inhibitor (Mdivi1) blocked LPS-ATP-stimulated DRP1 phosphorylation, reduced mitochondrial fragmentation, and ROS overproduction. Consistently, CHS diminished LPS-ATP-induced NLRP3-TXNIP interaction and inflammasome assembly, thereby reducing cellular membrane rupture and pyroptotic cell death, whereas DRP1 overexpression exerted the opposite effect.
SIGNIFICANCE: CHS represents a promising therapeutic candidate for septic cardiomyopathy by targeting DRP1-mediated mitochondrial dynamics and the NLRP3 inflammasome.

Keywords:  Chikusetsu saponin IVa; DRP1; Mitochondrial dysfunction; NLRP3 inflammasome; Pyroptosis; Septic cardiac dysfunction

DOI:  https://doi.org/10.1016/j.lfs.2026.124509
Mitochondrion. 2026 Jun 03. pii: S1567-7249(26)00063-2. [Epub ahead of print] 102173

Heart failure and mitochondrial dynamics: Role of intracellular angiotensin and emerging therapeutics.

Pranav Panchbhai, Satnam Singh, Gauri Chaturvedi, Nandini Dubey, Prabhkar Singh, Neeraj Prakh, Upendra Baitha, Ved Prakash, Rajiv Narang, Devendra K Agrawal, Harlokesh Narayan Yadav.

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide despite significant advances in neurohumoral therapies targeting the renin-angiotensin-aldosterone (RAAS). Although RAAS inhibition improves survival and limits adverse cardiac remodelling in failing hearts, mitochondrial dynamic dysfunction persists in a larger proportion of treated patients, indicating an intracellular signalling mechanism that sustains the pathological remodelling in these patients. Emerging evidence shows a shift toward a fission-dominant mitochondrial phenotype, acting as a critical feature of a failing heart. Angiotensin II (Ang II), beyond its classical endocrine actions, activates a network of calcium- and redox-dependent intracellular signalling pathways that converge on the mitochondrial fission machinery. Many of these components are incompletely inhibited by the conventional RAAS blockade, providing a mechanistic basis for RAAS escape and persistent mitochondrial dysfunction. This review highlights the mechanism underlying the temporal stabilization of fission-dominant mitochondrial phenotype, and discusses the opportunity to target mitochondrial dynamics as a complementary therapeutic strategy. Reframing angiotensin signalling through the lens of mitochondrial dysregulated dynamics may help overcome the limitations of current heart failure therapies.

DOI: https://doi.org/10.1016/j.mito.2026.102173
Mol Med Rep. 2026 Aug;pii: 220. [Epub ahead of print]34(2):

[Corrigendum] Electroacupuncture at GV20‑GB7 regulates mitophagy to protect against neurological deficits following intracerebral hemorrhage via inhibition of apoptosis.

Ruiqiao Guan, Zhihao Li, Xiaohong Dai, Wei Zou, Xueping Yu, Hao Liu, Qiuxin Chen, Wei Teng, Peng Liu, Xiaoying Liu, Shanshan Dong.

  Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, in comparing the bar charts shown in Fig. 2D and F on p. 5 representing the quantification of the western blot data featured in Fig. 2C and E respectively, these bar charts were strikingly similar, suggesting that the same chart may have erroneously been included in this figure twice to represent the different experimental conditions. The authors have re‑examined their original data, and realize that the bar chart that was correctly shown for Fig. 2F was erroneously duplicated in the figure to show the quantification of the data in Fig. 2D. The corrected version of Fig. 2, now showing the correct data for the bar chart in Fig. 2D, is shown on the next page. Note that this error did not affect the overall conclusions reported in the paper. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this. They also apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 24: 492, 2021; DOI: 10.3892/mmr.2021.12131].

Keywords:  apoptosis; autophagy; electroacupuncture; intracerebral hemorrhage; mitophagy

DOI:  https://doi.org/10.3892/mmr.2026.13930
Int Immunopharmacol. 2026 May 30. pii: S1567-5769(26)00800-3. [Epub ahead of print]184 116954

Codonopsis pilosula as the sovereign herb in Shenling Baizhu formula ameliorates DSS-induced ulcerative colitis via spermidine-AMPK-mediated mitophagy to inhibit the cGAS-STING inflammatory axis.

Xiaohu Xi, Jiankuan Li, Yingjing Wang, Yan Ni, Jiangtao Zhou, Lingya Cao, Wei Wei, Jianping Gao.

   BACKGROUND: Dextran sulfate sodium-induced ulcerative colitis is featured by excessive intestinal inflammation and disrupted mucosal immune homeostasis. Codonopsis pilosula is the sovereign herb in Shenling Baizhu Formula for ulcerative colitis therapy, and Codonopsis pilosula polysaccharides are its key active components, while their immunomodulatory effects and molecular mechanisms in Shenling Baizhu Formula against ulcerative colitis remain elusive. This study explored the critical role of Codonopsis pilosula polysaccharides and the spermidine-AMPK-mediated mitophagy-cGAS-STING inflammatory axis in regulating intestinal inflammation and ameliorating ulcerative colitis.
METHODS: A dextran sulfate sodium-induced ulcerative colitis mouse model was established to evaluate the indispensable role of Codonopsis pilosula polysaccharides in Shenling Baizhu Formula. Ultra-high performance liquid chromatography metabolomics and 16S ribosomal RNA sequencing were performed to identify key metabolites and gut microbiota. In vitro dextran sulfate sodium-induced ulcerative colitis cellular models (human colorectal adenocarcinoma Caco-2 and human normal colonic epithelial NCM460 cells) were constructed to validate the regulatory mechanism of spermidine on AMPK-mediated mitophagy, inflammatory balance and intestinal epithelial injury.
RESULTS: Codonopsis pilosula polysaccharides were essential for the anti-ulcerative colitis efficacy of Shenling Baizhu Formula: removal of Codonopsis pilosula significantly aggravated colonic pathological lesions, intestinal inflammatory responses and oxidative stress in ulcerative colitis mice, whereas Codonopsis pilosula polysaccharides supplementation reversed these abnormal phenotypes (P < 0.05). Metabolomics and microbiomics confirmed that Codonopsis pilosula polysaccharides exerted therapeutic effects via spermidine (a key metabolite in glutamate metabolism pathway) and Muribaculaceae. Critically, in vitro dual-cell experiments verified that spermidine activated AMPK-mediated mitophagy to directly inhibit the hyperactivation of cGAS-STING inflammatory axis, thereby restoring intestinal inflammatory homeostasis and alleviating epithelial cell injury in ulcerative colitis.
CONCLUSION: Codonopsis pilosula polysaccharides extracted from the sovereign herb Codonopsis pilosula in Shenling Baizhu Formula ameliorate dextran sulfate sodium-induced ulcerative colitis, and the core mechanism depends on spermidine-triggered AMPK-mediated mitophagy to suppress the cGAS-STING inflammatory signaling axis, which plays a pivotal role in regulating intestinal immunity and repairing mucosal epithelial damage.

Keywords:  AMPK; Codonopsis pilosula polysaccharides; Mitophagy; Spermidine; Ulcerative colitis; cGAS-STING

DOI:  https://doi.org/10.1016/j.intimp.2026.116954
Arthritis Res Ther. 2026 Jun 02.

Targeting the SARM1-cADPR-Ca2+ pathway attenuates mitochondrial fragmentation and osteoarthritis progression.

Yu Gu, Xin-Hao Zhao, Bai-Zhou Xing, Biao Wu, Rong Peng, Chang-Qing Li, Hai Lv, Hua-Ding Lu.

   INTRODUCTION: Osteoarthritis (OA) is a prevalent degenerative joint disease accompanied by increased number of senescent chondrocytes. Mitochondrial dysfunction is a well-established hallmark of chondrocyte senescence in OA pathogenesis. Sterile α and Toll/Interleukin-1 Receptor motif-containing 1 (SARM1), known to drive mitochondrial impairment in various cell types, has not been thoroughly investigated in the context of chondrocyte aging or OA.
METHODS: We established a doxorubicin (DOX)-induced senescence model in primary mouse chondrocytes. Gain- and loss-of-function approaches were employed using siRNA-mediated knockdown and lentiviral overexpression of SARM1, followed by assessment of senescence markers, mitochondrial function, and morphology. To investigate the mechanistic pathway, exogenous cyclic ADP-ribose (cADPR) and its specific inhibitor 8-Br-cADPR were applied, with subsequent evaluation of intracellular calcium dynamics and Drp1 translocation to mitochondria. We next tested the efficacy of blocking this SARM1/cADPR axis both ex vivo on human femoral head tissue as well as in an experimental OA mouse model.
RESULTS: Chondrocytes isolated from human OA cartilage and aged murine cartilage showed increased expression of SARM1. Knockdown of SARM1 reduced DOX-induced chondrocyte senescence and mitochondrial dysfunction, while overexpression of wild-type but not catalytic-inactive SARM1-TIR domain mutant (TIR-E642A) induced intrinsic apoptosis and mitochondrial fragmentation. Exogenous cADPR recapitulated senescence and mitochondrial fragmentation, whereas treatment with 8-Br-cADPR abolished SARM1-dependent effects. Mechanistically, SARM1-generated cADPR increased intracellular calcium levels, triggering Drp1 phosphorylation at Ser616 and dephosphorylation at Ser637, thereby resulting in Drp1-FIS1 interaction and mitochondrial fission. Interestingly, pharmacological or genetic inhibition of the SARM1/cADPR pathway ameliorated cartilage degradation in the experimental OA model.
CONCLUSION: We show that SARM1 mediates mitochondrial fragmentation by activating cADPR-dependent calcium signaling, which in turn promotes Drp1 binding to FIS1. This suggests an unappreciated role for the SARM1-cADPR pathway in OA etiology and presents this pathway as an attractive candidate to be targeted therapeutically.

Keywords:  Chondrocyte senescence; Drp1; Mitochondrial fragmentation; Osteoarthritis; SARM1; cADPR

DOI:  https://doi.org/10.1186/s13075-026-03837-3
Mater Today Bio. 2026 Jun;38 103249

Provoking disulfidptosis-enhanced mitophagy by manganese-based nanoplatform via regulating cellular energy supply and redox homeostasis.

Zhenying Diao, Bin Feng, Yanfei Fu, Youcheng Liang, Long Qiu, Jianbo Sun, Yanlei Liu, Daxiang Cui, Ting Yin.

  Metabolic reprogramming and reinforcing redox defense mechanisms in tumors remains major obstacles to oxidative stress therapies in Non-small cell lung cancer (NSCLC). To address these obstacles, we strategically targeted cystine transporter SLC7A11, which plays a central role in cellular redox homeostasis. Herein, guided by bulk RNA-sequencing (RNA-seq) analysis, we identified that concurrent activation of SLC7A11 and inhibition of glucose transporter GLUT1 synergistically delays NSCLC progression. We introduced an effective strategy to effectively target SLC7A11 and GLUT1 for synergistic chemodynamic therapy (CDT) and disulfidptosis. A RNA-seq-guided nanoplatform was constructed from manganese dioxide (HMnO2) with hollow structures and loaded with GLUT1 inhibitor Bay876 (HMnO2@Bay). Upon tumor cell uptake, HMnO2 continuously generates cytotoxic hydroxyl radicals through Fenton-like reaction and activates the expression of SLC7A11. The Bay876 released from the nanoplatform blocks glucose uptake, downregulates NADPH supplementation, and disrupts the SLC7A11-mediated GSH synthesis antioxidant pathway. This boosts disulfidptosis via increased cystine accumulation while concurrently enhancing CDT through the attenuation of GSH-mediated ROS exhaustion. Additionally, RNA-seq explored changes in the transcriptome of tumor cells treated with HMnO2@Bay, revealing that the synergistic therapy of CDT and disulfidptosis promotes mitophagy in tumor cells. Comprehensive in vitro and in vivo evaluations reveal the treatment effectively suppresses tumor growth with minimal systemic toxicity. This study provides a promising NSCLC therapy paradigm to induce disulfidptosis-enhanced mitophagy by simultaneously targeting oxidative and glucose dyshomeostasis.

Keywords:  Disulfidptosis; Metabolic regulation; Mitophagy; RNA-Sequencing; Synergistic therapies

DOI:  https://doi.org/10.1016/j.mtbio.2026.103249
Cell Prolif. 2026 Jun 04. e70237

High Uric Acid Promotes Stem Leydig Cell Senescence by CCDC90B Mediates Mitochondrial Quality Control Imbalance.

Jiayu Huang, Ao Wang, Xiangyu Li, Peng Huang, Kaixuan Zeng, Lu Sun, Moxuan Li, Yixiang Chen, Jiancheng Wang.

  Hyperuricemia is a common metabolic disease and an important risk factor for low testosterone levels in men. The functional homeostasis of stem Leydig cells (SLCs) is crucial for maintaining testosterone levels. However, the potential molecular mechanism of how high uric acid (UA) levels affect SLC function remains to be elucidated. Here, we reveal that at the single-cell RNA sequencing level, SLCs exhibit senescence under high UA conditions. Mechanistically, UA binds to CCDC90B, leading to its significant accumulation within cells. This exacerbates the influx of calcium ions into mitochondria, resulting in mitochondrial quality control (MQC) imbalance. In addition, at the level of organoids and transgenic mice, we observe SLC senescence is alleviated and considerable testosterone recovery after AAV8-CCDC90B treatment. In summary, these results indicate that SLC senescence under high UA is regulated in a MQC-dependent manner, with CCDC90B being a key regulatory target. Meanwhile, AAV-mediated gene therapy may offer a promising therapeutic approach for patients with low testosterone levels.

Keywords:  AAV; CCDC90B; cellular senescence; hyperuricemia; mitochondrial quality control; stem Leydig cells; testosterone; uric acid

DOI:  https://doi.org/10.1111/cpr.70237
Biochim Biophys Acta Biomembr. 2026 Jun 03. pii: S0005-2736(26)00049-0. [Epub ahead of print] 184546

Consequences of defective mitochondrial protein import: From targeting signals to pathology.

Maya Cielo Cornejo, Sandy Che-Eun S Lee, Shaya Smith, Carla M Koehler.

  Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.

Keywords:  Mitochondria; Mitochondrial disorders; Mitochondrial protein import; Mitochondrial protein processing; Mitochondrial targeting sequence; Proteostasis; TIM23 complex; TOM complex

DOI:  https://doi.org/10.1016/j.bbamem.2026.184546
Curr Med Chem. 2026 May 29.

MFF Promotes Aggressive Phenotypes and Immunosuppression in Lung Adenocarcinoma via Mitochondrial Dysregulation.

Xiao-Xin Pu, Bao-Yi Liu, Yu-Wen Xue.

   INTRODUCTION: Lung Adenocarcinoma (LUAD) remains a leading cause of cancer mortality, driving the need for novel prognostic markers and therapeutic targets. Mitochondrial dynamics, particularly fission, have emerged as a crucial regulator of tumor progression. Emerging evidence highlights the interplay between mitochondrial proteins and immune modulation, yet the role of Mitochondrial Fission Factor (MFF) in shaping the tumor immune microenvironment, particularly its involvement in non-canonical immune checkpoints, remains largely unexplored in LUAD. Herein, we investigate the expression and clinical significance of MFF in LUAD, and explore its potential associations with mitochondrial dynamics, metabolic reprogramming, and immune modulation.
METHODS: Gene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) LUAD cohort for bioinformatics analysis. Validation at the protein level was performed using Immunohistochemistry (IHC) on a Tissue Microarray (TMA) containing 42 evaluable paired LUAD and adjacent normal tissues. Bioinformatics analyses included differential expression, survival (Kaplan-Meier, Cox regression), Protein-Protein Interaction (PPI) networks, Gene Set Enrichment Analysis (GSEA), and immune infiltration profiling.
RESULTS: MFF was significantly overexpressed in LUAD at both transcript and protein levels and correlated with advanced disease stages, male gender, and poor survival. It served as a robust prognostic biomarker even in early-stage and node-negative subgroups. Beyond its expected association with mitochondrial dynamics regulators (DNM1L/DRP1, MFN1), MFF expression strongly correlated with a hyperactive OXPHOS transcriptional program, identifying a distinct metabolic phenotype. MFF high tumors were characterized by a distinctive immune checkpoint landscape, with reduced expression of PD-1 and CTLA-4, but marked upregulation of B7-H3 (CD276), coupled with broad suppression of immune infiltration and the antigen presentation machinery.
DISCUSSION: Our findings establish MFF as a multifunctional hub linking mitochondrial plasticity to metabolic adaptation and immune evasion in LUAD. The strong OXPHOS association suggests MFF-high tumors may act as metabolic sinks, creating a nutrient-deprived microenvironment hostile to infiltrating immune cells. The distinct B7-H3-dominant checkpoint profile further defines a non-inflamed "immune desert" phenotype, offering a potential explanation for resistance to conventional PD-1/CTLA-4 blockade. While our data do not establish causation, we propose three testable hypotheses for this immunosuppressive phenotype: metabolic competition, shared upstream regulation (e.g., androgen receptor signaling), and stress-induced checkpoint switching.
CONCLUSION: MFF drives LUAD progression by orchestrating mitochondrial plasticity and fostering a metabolically distinct, B7-H3-dominant "cold" tumor microenvironment. This positions MFF as a robust prognostic biomarker and identifies MFF-high patients as a specific subgroup that may resist conventional immunotherapy but could benefit from emerging B7-H3-directed therapies, including antibody-drug conjugates or chimeric antigen receptor (CAR)-T cells. Further functional studies are warranted to distinguish whether MFF actively regulates these processes or serves as a marker of this aggressive tumor niche.

Keywords:  LUAD; MFF; immunosuppressive microenvironment; metabolic reprogramming.; mitochondrial fission; prognostic biomarker

DOI:  https://doi.org/10.2174/0109298673449613260514105738
Chin Med. 2026 Jun 04. pii: 161. [Epub ahead of print]21(1):

Hyperoside protects against poly-GR-mediated neurodegeneration via regulation of mitochondrial fission and oxidative stress in C9orf72-associated ALS.

Wen-Chi Hsieh, Chun-Yu Lin, Hsuan-Cheng Wu, Eddie Feng-Ju Weng, Shao-Ming Wang.

   BACKGROUND: Arginine-rich poly-glycine-arginine (poly-GR), a toxic dipeptide repeat protein generated from C9orf72 hexanucleotide repeat expansion, drives mitochondrial dysfunction, oxidative stress, and neuronal loss in amyotrophic lateral sclerosis (ALS). Hyperoside, a bioactive flavonoid, exhibits antioxidant and cytoprotective properties, but its therapeutic relevance to C9orf72-associated ALS remains unclear.
PURPOSE: To determine whether hyperoside attenuates poly-GR-induced mitochondrial and oxidative injury and improves neuronal survival in cellular and animal models of C9orf72-ALS.
METHODS: A combined in vitro and in vivo experimental study using motor neuron-like cells and an AAV-mediated neonatal mouse model of poly-GR toxicity. NSC34 cells expressing EGFP-GR50 were analyzed for mitochondrial morphology, membrane potential, ROS generation, antioxidant signaling, and apoptosis using confocal microscopy, CellROX/MitoTracker assays, Western blot analysis, and viability testing. For in vivo assessment, neonatal mice received intracerebroventricular AAV9-EGFP-GR50 followed by intraperitoneal hyperoside (10 mg/kg). Survival, cerebral hemisphere length, and cortical NeuN⁺ neuron numbers were quantified.
RESULTS: Poly-GR expression induced pronounced mitochondrial fragmentation, reduced membrane potential, elevated ROS, and suppressed Nrf2/HO-1/GPx4 signaling, accompanied by increased Drp1 and reduced Opa1 expression. Hyperoside reversed these abnormalities by restoring mitochondrial integrity, normalizing the Drp1/Opa1 balance, enhancing Nrf2 nuclear accumulation, and increasing the expression of HO-1 and GPx4. Hyperoside also reduced cleaved caspase-3 and corrected the Bax/Bcl-2 ratio, improving cell viability under basal and oxidative stress conditions. In vivo, hyperoside modestly prolonged survival, increased cerebral hemisphere length, and significantly preserved cortical neuronal numbers in AAV9-EGFP-GR50 mice.
CONCLUSION: Hyperoside mitigates poly-GR-induced neurotoxicity by alleviating excessive mitochondrial fission, strengthening Nrf2-dependent antioxidant defenses, and suppressing apoptosis. These findings support hyperoside as a promising multi-target therapeutic candidate for C9orf72-associated ALS.

Keywords:   C9orf72-associated ALS; Hyperoside; Mitochondrial dysfunction; Nrf2; Oxidative stress

DOI:  https://doi.org/10.1186/s13020-026-01433-w
Nat Commun. 2026 Jun 05.

AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.

Yuqin Wang, Raksha K Rao, Trung Vu, Ayano Sekine, Zhengmei Mao, Nami McCarty.

Mitochondria and autophagy are fundamental yet distinct regulators of cellular homeostasis. Here, we identify AMC-F1 (Autophagy-Mitochondria Coupling Factor 1; formerly TRIM44) as a central integrator of mitochondrial bioenergetics and autophagy. Using Amcf1 knockout and knock-in mouse models, we demonstrate that AMC-F1 bidirectionally regulates these pathways: its loss reduces mitochondrial respiration and autophagic flux, whereas its overexpression promotes mitochondrial elongation and increases autophagy independently of nutrient stress. Transcriptomic analyses reveal AMC-F1-dependent regulation of mitochondrial biogenesis programs that engage autophagy, involving mitochondrial respiratory chain complex genes under basal conditions and mitochondrial organization factors under starvation-induced autophagy. Although dispensable under homeostasis, this coupling becomes essential during stress adaptation. In an acute liver-injury model, Amcf1 knock-in mice were fully protected, exhibiting elevated OPA1, reduced caspase-3 and PARP activation, and preserved Beclin 1. This functional duality reflects AMC-F1's ability to modulate the mitochondrial integrated stress response (mtISR), enabling adaptive ATF4 signaling while preventing maladaptive responses when stress exceeds a threshold. Autophagy upregulation by AMC-F1 is critical for fine-tuning the ISR and preserving cellular resilience. Together, our findings position AMC-F1 as a stress-responsive gatekeeper and a novel coordinator of mitochondrial-autophagy crosstalk, defining a cellular state primed for stress adaptation.

DOI: https://doi.org/10.1038/s41467-026-73841-3
Semin Hematol. 2026 May 09. pii: S0037-1963(26)00041-7. [Epub ahead of print]

Evolving insights into mitochondrial presence in RBC in sickle cell disease: Red blood cell and reticulocyte pathophysiology, therapeutic strategies, and future directions.

Yaw Ansong-Ansongton, Daisy Zapet Bamac, Angela Rivers.

  Recent advances in understanding sickle cell disease (SCD) pathophysiology have revealed the critical role of abnormal mitochondrial retention in mature erythrocytes. This comprehensive review examines how disrupted mitochondrial clearance contributes to disease progression through multiple mechanisms, including oxidative stress, metabolic dysfunction, and immune activation. We will review evidence from both human studies and animal models demonstrating that retained mitochondria remain functionally active and contribute to cellular damage. Furthermore, we will highlight emerging findings that active mitochondria in reticulocytes are also detrimental in SCD, exacerbating oxidative stress, and promoting premature cellular damage. This review examines therapeutic approaches targeting mitochondrial dysfunction, including pyruvate kinase activation and mitophagy enhancement strategies. Understanding these mechanisms provides new opportunities for therapeutic intervention in SCD and related disorders.

Keywords:  Erythrocyte mitochondrial retention; Mitochondria; Mitophagy; Reactive oxygen species; Sickle cell disease

DOI:  https://doi.org/10.1053/j.seminhematol.2026.05.003
Ecotoxicol Environ Saf. 2026 Jun 05. pii: S0147-6513(26)00646-9. [Epub ahead of print]322 120317

Hydramethylnon-induced pulmonary toxicity associated with necroptosis signaling and mitochondrial dysfunction in human bronchial epithelial cells.

Su Hwan Park, Tanya Bhatt, Hye Jin Yun, Eun Bin Lee, Eun Hee Ko, Min-Seok Kim, Wan-Seob Cho, Jong-Ho Lee.

  Insecticides have been applied in various household products, and our previous study showed that hydramethylnon (HM), among five classes tested, showed significant pulmonary toxicity in rats and human A549 cells. In this study, we investigated the underlying molecular mechanisms of HM-induced toxicity in human bronchial epithelial cells (HBECs) using BEAS-2B and 16HBE14o cells. In addition, these mechanisms were further confirmed in mice using an intratracheal instillation model. HM treatment induced cytotoxicity in both cell lines, characterized by cell cycle arrest, inhibition of cell proliferation, and cell death with apoptotic features. Notably, HM treatment triggered a rapid increase in necroptosis signaling, as evidenced by phosphorylation of receptor-interacting protein kinase (RIPK) 1 and mixed lineage kinase domain-like (MLKL), and subsequent necroptosis signaling at mitochondria. This activation disrupted mitochondrial homeostasis as evidenced by a reduction in mitochondrial content, as assessed by decreased translocase of outer mitochondrial membrane 20 (TOM20) fluorescence intensity, loss of mitochondrial DNA, reduced electron transport chain complex proteins, adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS), and induction of mitophagy. This necroptosis-associated mitochondrial dysfunction ultimately resulted in cell death with apoptotic features of HBECs. Consistently, intratracheal instillation of HM in mice induced acute lung injury with pronounced necroptosis signaling, mitochondrial loss in airway bronchial epithelial cells, and increased cell death with apoptotic features. These findings demonstrate that HM induces cytotoxicity in bronchial epithelial cells associated with necroptosis signaling and mitochondrial dysfunction in vitro and in vivo, revealing a novel mechanism of inhalation toxicity and highlighting the potential risks of HM-containing household products.

Keywords:  Bronchial epithelial cell; Hydramethylnon; Inhalation toxicity; Mitochondrial homeostasis; Necroptosis

DOI:  https://doi.org/10.1016/j.ecoenv.2026.120317
Redox Biol. 2026 May 30. pii: S2213-2317(26)00240-5. [Epub ahead of print]95 104242

CHK1 activates mitophagy to attenuate cardiac aging via inhibiting AHSA1-ubiquitination.

Peng Jing, Liu-Hua Zhou, Shu-Xuan Chen, Jia-Yi Chen, Ling-Feng Gu, Tong-Tong Yang, Si-Bo Wang, Chong Du, Yi-Xi Chen, Qi-Ming Wang, Lian-Sheng Wang, Hao Wang.

  With the acceleration of global population aging, the progressive deterioration of cardiac structure and function has become a critical determinant of cardiovascular health, presenting a significant public health challenge. Checkpoint kinase 1 (CHK1), a key cell cycle checkpoint protein, plays an essential role in various biological processes by mediating signaling cascades. While CHK1 has been shown to be important for heart regeneration, its role in the aging process of the heart remains unclear. In this study, we investigated the alterations in CHK1 expression in aging hearts and elucidated the underlying regulatory mechanisms. In both in vivo and in vitro models, CHK1 expression was significantly downregulated during aging. To assess its functional role, we generated cardiomyocyte-specific CHK1 overexpression and knockout mice and compared their cardiac performance. We found that CHK1 overexpression alleviated age-associated cardiac dysfunction, while CHK1 knockout worsened cardiac function in aged mice. Furthermore, CHK1 overexpression significantly attenuated doxorubicin (DOX)-induced acutely senescence in adult mouse cardiomyocytes (AMCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Mechanistic studies revealed that CHK1 overexpression delayed cardiac aging by activating heat shock protein 90 (HSP90)-mediated mitophagy. Immunoprecipitation and mass spectrometry (IP-MS) analyses demonstrated that CHK1 directly interacts with the activator of HSP90 ATPase homolog 1 (AHSA1), thereby suppressing TRIM8-mediated ubiquitination and degradation, facilitating AHSA1-HSP90 complex formation, and enhancing HSP90 ATPase activity. Overall, our results suggest that CHK1 overexpression activates mitophagy via the AHSA1-HSP90 pathway to mitigate cardiac aging. This study highlights the critical role of CHK1 in cardiac aging and proposes a potential therapeutic strategy for aging-associated cardiomyopathy and heart failure.

Keywords:  AHSA1; CHK1; Cardiac aging; HSP90; Mitophagy

DOI:  https://doi.org/10.1016/j.redox.2026.104242
Front Cardiovasc Med. 2026 ;13 1775592

From mitochondrial zonation to immune dysregulation: a mechanistic axis in diabetic cardiomyopathy.

Jiahui Chen, Linghua Fu, Jing Zhang, Rui Ding, Hanbin Zhang, Gaosi Xu, Jinzhu Hu, Pingping Yang.

  Diabetic cardiomyopathy (DbCM) is characterized by early diastolic dysfunction, myocardial fibrosis, and progressive energetic failure, in which mitochondria dysfunction have a central role. Although mitochondrial dysfunction is well established in DbCM, emerging spatially resolved data indicate that cardiomyocytes contain functionally distinct mitochondrial subpopulations with differential susceptibility to metabolic stress. In this Review, we synthesize mechanistic and translational evidence and propose a unifying, testable hypothesis. Selective remodeling of membrane lipids and cristae destabilization may render specific mitochondrial subsets "early-damaged." These mitochondria produce sustained mitochondrial reactive oxygen species (mtROS), release oxidized mtDNA or mitochondrial-derived vesicles (MDVs), and subsequently activate innate immune pathways. We particularly emphasize distinct mitochondrial subpopulations, including subsarcolemmal (SSM), interfibrillar (IFM), and perinuclear mitochondria (PNM). Finally, we posit a proof-of-concept translational roadmap involving biomarker-guided, spatially informed preclinical endpoints and targeted interventions. Conceptualizing DbCM as a disease of mitochondrial heterogeneity and maladaptive mtROS-mtDNA-innate immune coupling reorients therapeutic strategy from global antioxidant suppression toward precision, organelle- and location-specific modulation.

Keywords:  diabetic cardiomyopathy; innate immunity; mitochondrial heterogeneity; mitochondrial reactive oxygen species; mitophagy; myocardial fibrosis

DOI:  https://doi.org/10.3389/fcvm.2026.1775592
Aging Cell. 2026 Jun;25(6): e70573

Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.

Grant R Laskin, Baylah R Mazonson, LaDora V Thompson.

Mitochondrial dysfunction, impaired proteostasis, and reduced stress resistance and resilience are aging hallmarks. At the core of these hallmarks, the mitochondrial unfolded protein response (mtUPR) is a transcriptional pathway that restores mitochondrial proteostasis in response to proteotoxicity. Although the mtUPR is well studied in invertebrates and cell culture models, how the mtUPR is engaged in aged mammalian tissue is poorly defined. Here, we defined the extent to which repeated physical stress initiates mtUPR transcription in aged mouse skeletal muscle and assessed candidate regulatory mechanisms in vivo. Aged muscle exhibited reduced mitoprotective chaperone and protease availability and greater carbonylation of intermyofibrillar mitochondria relative to young muscle, suggesting diminished proteostatic reserve and increased oxidative burden. Short-term physical stress induced a greater initiation of mtUPR genes in aged muscle than young muscle, coinciding with reduced physiological reserve. Physical stress shifted ATF5 localization from the mitochondria to the nucleus in the muscle of both ages, whereas CHOP mRNA and nuclear localization were selectively elevated in aged muscle. Mechanistically, we show mitochondrial reactive oxygen species (mtROS) contribute to mtUPR initiation in aged skeletal muscle. Using in vivo ChIP-qPCR and in vitro knockdown/inhibition experiments, we provide support for CHOP as a redox-sensitive factor contributing in part to the enhanced mtUPR initiation in aged mouse muscle, potentially linked to JNK signaling. Collectively, these data suggest reduced mitochondrial proteostatic reserve and mtROS signaling in aged muscle contribute to an amplified mtUPR transcriptional response following repetitive physical stress, providing the foundation to explore the mtUPR in mammalian aging.

DOI: https://doi.org/10.1111/acel.70573
J Nanobiotechnology. 2026 Jun 04.

M2 microglia-derived migrasome-enriched extracellular vesicles restore mitochondrial homeostasis to orchestrate neurovascular unit recovery after ischemic stroke.

Yuanjia Zhang, Jie Wu, Leyi Liu, Yiqian Zhu, Jierui Zhang, Jinghong Xu, Xuefeng Shi, Yu Yu, Chao Wang, Jiajing Xiao, Xuanchenye Zhang, Zhaorong Li, Wenqi Huang, Wenzhi Li, Zhongxing Wang, Tingting Li.

  Ischemic stroke is a major cause of disability with few treatment options available. Microglia-driven neuroinflammation contributes significantly to stroke pathology, and promoting anti-inflammatory microglial phenotypes represents a promising strategy. Migrasomes are newly discovered organelles mediating intercellular communication, yet their role in ischemic stroke remains unexplored. This study demonstrates that M2 microglia-derived migrasome-enriched extracellular vesicles (EVs) exert potent neuroprotection in both OGD/R cell models and MCAO mice. These migrasome-enriched EVs were efficiently internalized by microglia, astrocytes, neurons, and microvascular endothelial cells, promoting microglial M2 polarization, suppressing astrocytic aberrant activation, reducing neuronal apoptosis, and enhancing angiogenesis. Intracerebral administration of M2 microglia-derived migrasome-enriched EVs significantly reduced infarct volume, ameliorated cerebral edema, improved cerebral blood flow, and accelerated neurological and cognitive recovery without detectable toxicity. Mechanistically, migrasome-enriched EVs activated the cAMP/EPAC1/Rap1 signaling pathway in microglia, leading to restored mitochondrial homeostasis. Collectively, these findings identify M2 microglia-derived migrasome-enriched EVs as novel intercellular messengers that orchestrate neurovascular unit recovery after ischemic stroke, positioning migrasome-enriched EVs as promising candidates for stroke therapy.

Keywords:  Ischemic stroke; Microglia polarization; Migrasome-enriched extracellular vesicles; Mitochondrial homeostasis; Neurovascular unit recovery

DOI:  https://doi.org/10.1186/s12951-026-04643-4
Naunyn Schmiedebergs Arch Pharmacol. 2026 Jun 06.

Dietary phytoestrogen ameliorates ovarian toxicant-induced neurotoxicity: mechanistic and metabolic insights.

Ambika Shandilya, Suhas Hajare, Dube Aakash Arwind, Chander Kant Giri, Rahul Gajbhiye, V Ravichandiran, Vipan Kumar Parihar.

  Premature ovarian insufficiency (POI) poses serious neurological risks such as mood disturbances, cognitive decline, early brain structural changes, neural degeneration, and a heightened risk of dementia and AD in women. This study aims to investigate cognitive performance, mitochondrial malfunction, and persistent neuroinflammation in a mouse model of premature ovarian failure induced by ovatoxin vinylcyclohexene diepoxide (VCD), as well as the potential use of dietary phytoestrogen therapy to combat the accelerated brain ageing-like phenotype and chronic inflammation associated with ovarian insufficiency. The data from our neurobehavioural evaluations showed impaired object recognition memory, along with enhanced anxiety and depression in the VCD-intoxicated mice. This was accompanied by a water maze assessment, which indicates that long-term estrogen depletion negatively affected spatial learning and memory retrieval. This is demonstrated by the increased time required for VCD mice to locate the hidden platform and their inability to find the virtual platform during the memory retrieval assessment. In VCD-challenged mice, there were clear signs of compromised learning and memory across the behavioural tests, along with impaired mitochondrial complexes and increased β-amyloid protein expression. Furthermore, in conjunction with reduced estrogen levels, VCD mice showed enhanced neuronal inflammation, as evidenced by heightened expression of neuroinflammatory mediators, including HMGB1, TLR-4, NF-kappa B, CD68 and TREM2. Furthermore, our study has shown that a phytoestrogen diet can restore compromised mood and memory functions. The improvements in learning, memory, and cognitive abilities associated with this dietary intervention were evidenced by reduced neuroinflammation, restored mitochondrial respiratory complexes, enhanced neurotrophic factor levels, and decreased β-amyloid protein expression. Consequently, the current results provide preliminary support for the hypothesis that a diet rich in phytoestrogens could be a viable strategy to mitigate accelerated brain ageing and address mood and memory challenges associated with ovarian insufficiency.

Keywords:  Accelerated ovarian failure; Brain metabolomics; Cognitive impairment; Mitochondrial dynamics; Neuroinflammation; Phytoestrogen therapy

DOI:  https://doi.org/10.1007/s00210-026-05515-2
Cell Rep. 2026 Jun 01. pii: S2211-1247(26)00456-0. [Epub ahead of print]45(6): 117378

Activity-regulated circSamm50 modulates mitochondrial dynamics and spine structural plasticity.

Kaushik Chanda, Ojasee Bapat, Jenna Lynne Wingfield, Yosef Avchalumov, Melissa Kazantzis, Jackson P Carter, Neelam Sharma, Ronald Davis, Jason X-J Yuan, Vidhya Rangaraju, Sathyanarayanan V Puthanveettil.

  Circular RNAs (circRNAs) are highly enriched in the brain, yet their functional contributions to synaptic plasticity remain unclear. Here, we uncover a plasticity-induced circRNA that links mitochondrial regulation to activity-dependent spine remodeling. Chemical long-term potentiation in primary hippocampal neurons identified circSamm50, derived from Samm50, which encodes a mitochondrial outer membrane protein, as robustly upregulated. circSamm50 sequesters miR-186-5p to sustain Samm50 mRNA levels, thereby coupling circRNA signaling to mitochondrial gene regulation. Acute CRISPR-Cas13-mediated depletion of circSamm50 disrupted mitochondrial morphology, transport, and bioenergetics across neuronal compartments. Functionally, circSamm50 loss impaired excitatory synaptic transmission, reduced spine density, and compromised two-photon glutamate uncaging-induced structural plasticity. Together, our findings uncover circSamm50 as a plasticity-modulated circRNA that coordinates mitochondrial function with activity-dependent spine remodeling, revealing a mechanism by which circRNAs couple metabolic control to synapse function and structural plasticity.

Keywords:  CP: molecular biology; CP: neuroscience; LTP; circular RNA; gene networks; hippocampal neurons; mitochondria; structural plasticity; synaptic transmission

DOI:  https://doi.org/10.1016/j.celrep.2026.117378