Suoquan Yishen formula attenuates ectopic lipid deposition in diabetic kidney disease by inhibiting UBC9-mediated SUMO1 modification of DRP1.

Targeting HSP90 suppresses STAT1/CCL8-driven inflammation and mitigates mitochondrial dysfunction to attenuate hypertension-induced atrial fibrillation.

EBV-driven rewiring of Drp1-Mediated mitophagy exacerbates trichloroethylene-induced hypersensitivity syndrome.

Endothelial Arg2 regulates HIMM-induced mitochondrial hyperfission via affecting arginine metabolism.

HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease.

CircCramp1l targets the miR-532-3p/HMGB1/Drp1 axis to regulate allergic rhinitis.

Nsun2-mediated m5C methylation of Ncor1 exacerbates sepsis-induced cardiomyopathy by promoting mitochondrial dysfunction.

Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1(DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.

ABSTRACT Fibrous dysplasia (FD) is a bone mesenchymal stromal cells (BMSCs)-derived disorder caused by GNAS gene mutation, characterized by excessive fibrous tissue proliferation in bone and the formation of immature trabecular bone. Although impaired osteogenesis of BMSCs is central to FD pathogenesis, the underlying mechanism remains largely elusive. Here we demonstrate that hyperactivation of the cAMP-PRKA/PKA signaling axis disrupts mitochondrial homeostasis through impaired mitophagy, ultimately leading to diminished amorphous calcium phosphate (ACP) secretion and consequent mineralization failure in FD. Mechanistically, in FD BMSCs, PRKA activation inhibits DNM1L/DRP1 recruitment to mitochondria through phosphorylation at S637, thereby suppressing mitochondrial fission. Consequently, excessive mitochondrial fusion leads to an elevated mitochondrial membrane potential, impaired mitophagy, and diminished ACP release. Collectively, our findings reveal a novel signaling nexus linking cAMP-PRKA signaling, mitochondrial dynamics, and biomineralization processes in FD pathogenesis, providing critical insights into the molecular basis of this disorder.

Drug-induced mitochondrial toxicity is a major contributing factor to cardiotoxicity, which can cause drug attrition and adverse cardiac events. To assess the toxicity of anti-inflammatory agents, we used adult human primary cardiomyocytes (hPCMs) to screen 18 clinically available anti-inflammatory drugs in a high-content manner, and revealed widespread mitochondrial dysfunction without affecting cell viability. Nabumetone, a representative nonsteroidal anti-inflammatory drug with profound mitochondrial toxicity, induced mitochondrial fission, inhibited mitophagy, and impaired both electrophysiological and metabolic functions in adult hPCMs. Mechanistically, we uncovered that nabumetone (Nab) exerted its toxic effects through the prostaglandin E2- E-type prostanoid receptor 4 (PGE2-EP4) pathway, which was essential for its anti-inflammatory functions. To find an alternative route to ameliorate mitochondrial damage, we identified SIRT3 as a downstream target of nabumetone. Its mRNA, protein, and activity levels were significantly reduced upon nabumetone treatment. SIRT3 activator honokiol exhibited protective potential against NSAID-induced mitochondrial toxicity both in hPCMs and in nabumetone-treated mice. Finally, through screening mitochondrial liability in various common cardiomyocyte models, we identified mitochondrial abundance as an important determinant of the sensitivity of cells towards mitochondrial toxicants. Our study demonstrates the vast presence of mitochondrial dysfunction in human adult cardiomyocytes imposed by clinically used anti-inflammatory drugs, and identified both toxicity and protective pathways that may serve future therapeutic purposes.

Research on cartilage repair in the knee joint is crucial for treating knee arthritis or injuries. The application of mesenchymal stem cells (MSCs) for cartilage tissue regeneration represents a promising therapeutic approach. Among the critical aspects in cartilage formation, the enhancement of MSC chondrogenic differentiation stands as a pivotal challenge. WDR63 is a cytoplasmic dynein that plays a significant role in promoting stem cell differentiation and is closely associated with the cytoskeleton and energy metabolism processes. In the current study, our objective is to elucidate the phenotypic manifestations and mechanisms of WDR63 in relation to its chondrogenic differentiation function in MSCs. Stem cells from apical papilla (SCAP) were used. The Alcian Blue staining technique, pellet culture system, and cell transplantation in rabbit knee cartilage defects were employed to assess the chondrogenic differentiation capabilities of MSCs. Western blot and real-time RT-PCR were utilized to investigate the molecular mechanisms involved. In vitro, WDR63 overexpression in SCAPs enhanced chondrogenic differentiation, as evidenced by upregulating collagen type II (COL2), collagen type V (COL5), and sex-determining region Y box protein 9 (SOX9), and robust pellet formation, whereas WDR63 knockdown produced opposite effects. In vivo, implantation of WDR63-overexpressing SCAP promoted cartilage repair in a rabbit osteochondral defect model, showing improved hyaline cartilage matrix deposition, higher COL2 expression, reduced collagen type X(COLX) expression, and increased collagen type Ι (COL1) expression in the subchondral bone. Mechanistically, WDR63 interacted and co-localized with vimentin (VIM), and its overexpression enhanced VIM expression and WDR63-VIM binding. WDR63 upregulates DRP1 expression, and rescues the Mdi-suppressed mitochondrial fission. WDR63 may promote chondrogenic differentiation of SCAPs by interacting with VIM and enhancing its expression, potentially through facilitating mitochondrial fission.

Quercetin alleviates LPS-induced inflammation and immunosuppression in broiler spleen via regulating the mtDNA/cGAS/STING axis.

HSP70 preserves brain microvascular endothelial integrity under heat stress associated with suppressed JNK-mediated apoptosis and mitophagy.

Atmospherically relevant PM2.5 promotes age-related muscle atrophy in an age-dependent manner.

From Tim4 to ischemic stroke: a mitochondrial pathway driving microglial M1 polarization.

Parkinson's disease (PD) lacks effective disease-modifying therapies, despite mitochondrial dysfunction being a key pathogenic factor. This study aimed to identify novel regulators of mitochondrial dynamics and explore their therapeutic relevance. Transcriptomic analysis was conducted on the substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. SN-specific lentiviral knockdown or overexpression of nucleoside diphosphate kinase 3 (NME3) was performed in mice. Motor behavior, dopaminergic neuron survival, mitochondrial ultrastructure, and reactive oxygen species (ROS) levels were assessed. Mitochondrial fission was pharmacologically inhibited using the Drp1 inhibitor Mdivi-1. RNA sequencing revealed a marked reduction of Nme3 in the SN of MPTP-treated mice. Nme3 knockdown in healthy mice induced PD-like motor deficits and dopaminergic neurodegeneration, mimicking the MPTP model. Mechanistically, NME3 deficiency disrupted mitochondrial fission-fusion balance, causing abnormal mitochondrial morphology, excessive ROS production, and neuronal injury. Mdivi-1 treatment significantly alleviated mitochondrial dysfunction and neurotoxicity. Conversely, SN-specific Nme3 overexpression in MPTP-treated mice improved motor performance and preserved dopaminergic neurons by suppressing pathological mitochondrial fission. NME3 is a previously unrecognized regulator of mitochondrial dynamics and a critical contributor to PD pathogenesis. Restoring mitochondrial fission-fusion balance through genetic or pharmacological approaches provides neuroprotection, highlighting NME3 as a promising target for disease-modifying PD therapies.

Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells.

The non-metabolic role of MTHFD2 in regulating mitochondrial fission-dependent mitophagy via stabilizing TOP2A mRNA in glioblastoma.

Effect of chronic intermittent hypoxia on apoptosis based on microbiome-based co-metabolomics.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of misfolded α-synuclein in the brain. Mitochondrial dysfunction and oxidative stress are factors contributing to the death of these neurons. Coenzyme Q10 (CoQ10) serve as an antioxidant and cofactor for mitochondrial enzymes, and its deficiency can exacerbate neurodegenerative processes in PD. However, the clinical efficacy of CoQ10 is limited by its low bioavailability and instability. Ubiquinol diacetate (CoQ10 Ac), an esterified form of CoQ10, shows improved pharmacokinetic properties and potential as a prodrug, converting into the reduced antioxidant form of CoQ10 by esterases in the body. This study aimed to investigate the antioxidant and neuroprotective effects of CoQ10 Ac compared to CoQ10 in SH-SY5Y cell line and Caenorhabditis elegans models of PD. CoQ10 Ac showed higher antioxidant activity than CoQ10 at both extracellular and intracellular levels, particularly in the membrane and cytosolic compartments. It exhibited superior neuroprotection against 6-hydroxydopamine toxicity, showing a greater ability to reduce the activation of caspase-3 and PARP1 compared to CoQ10. Both compounds decreased the increased ratio of mitochondrial fission protein, DRP1, to fusion protein, OPA1, induced by 6-hydroxydopamine in SH-SY5Y cells, enhancing OPA1 levels and promoting antiapoptotic death. However, CoQ10 Ac was more effective than CoQ10 in preserving mitochondrial structural integrity and mass. Additionally, both compounds significantly inhibited the aggregation of α-synuclein induced by 6-hydroxydopamine. Furthermore, CoQ10 Ac showed stronger neuroprotective effects than CoQ10 in C. elegans models of PD. It demonstrated greater anti-aggregant activity in C. elegans expressing human α-synuclein, suggesting higher bioavailability. These findings highlight CoQ10 Ac as a promising prodrug candidate and support further investigation in in vivo PD models.