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Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by many proteins to form a nucleoid that uniformly distributes within the mitochondrial matrix, which is essential for mitochondrial functions. Defects or mutations of mtDNA result in a range of diseases. Damaged mtDNA could be eliminated by mitophagy, and all paternal mtDNA are degraded by endonuclease G or mitophagy during fertilization. In this review, we describe the role and mechanism of mtDNA distribution and elimination. In particular, we focus on the regulation of paternal mtDNA elimination in the process of fertilization.

Mitochondrial cristae are critical for efficient oxidative phosphorylation, however, how cristae architecture is precisely organized remains largely unknown. Here, we discovered that Mic19, a core component of MICOS (mitochondrial contact site and cristae organizing system) complex, can be cleaved at N-terminal by mitochondrial protease OMA1 under certain physiological stresses. Mic19 directly interacts with mitochondrial outer-membrane protein Sam50 (the key subunit of SAM complex) and inner-membrane protein Mic60 (the key component of MICOS complex) to form Sam50–Mic19–Mic60 axis, which dominantly connects SAM and MICOS complexes to assemble MIB (mitochondrial intermembrane space bridging) supercomplex for mediating mitochondrial outer- and inner-membrane contact. OMA1-mediated Mic19 cleavage causes Sam50–Mic19–Mic60 axis disruption, which separates SAM and MICOS and leads to MIB disassembly. Disrupted Sam50–Mic19–Mic60 axis, even in the presence of SAM and MICOS complexes, causes the abnormal mitochondrial morphology, loss of mitochondrial cristae junctions, abnormal cristae distribution and reduced ATP production. Importantly, Sam50 displays punctate distribution at mitochondrial outer membrane, and acts as an anchoring point to guide the formation of mitochondrial cristae junctions. Therefore, we propose that Sam50–Mic19–Mic60 axis-mediated SAM–MICOS complexes integration determines mitochondrial cristae architecture.

Mitocbondrial fusion is a highly coordinated process that mixes and unifies the mitochondrial compartment for normal mitochondrial functions and mitochondrial DNA inheritance. Dysregulated mitochondrial fusion causes mitochondrial fragmentation, abnormal mitochondrial physiology and inheritance, and has been causally linked with a number of neuronal diseases. Here, we identified a diterpenoid derivative 15-oxospiramilactone （$3） that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfnl or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of $3. The inhibition of USP30 by $3 leads to an increase of non-degradative ubiquitination of Mfnl/2, which enhances Mfnl and Mfn2 activity and promotes mitochondrial fusion. Thus, through the use of an inhibitor of USP30, our study uncovers an unconventional function of non-degradative ubiquitination of Mfns in promoting mitochondrial fusion.

The strong nonlinearity of shallow-water waves significantly affects the dynamic response of floating offshore wind turbines (FOWTs), introducing additional complexity in motion behavior. This study presents a series of 1:80-scale experiments conducted on a 5 MW FOWT at a 50 m water depth, under regular, irregular, and focused wave conditions. The tests were conducted under regular, irregular, and focused wave conditions. The results show that, under both regular and irregular wave conditions, the platform’s motion and mooring tension increased as the wave period became longer, indicating a greater energy transfer and stronger coupling effects at lower wave frequencies. Specifically, in irregular seas, mooring tension increased by 16% between moderate and high sea states, with pronounced surge–pitch coupling near the natural frequency. Under focused wave conditions, the platform experienced significant surge displacement due to the impact of large wave crests, followed by free-decay behavior. Meanwhile, the pitch amplitude increased by up to 27%, and mooring line tension rose by 16% as the wave steepness intensified. These findings provide valuable insights for the design and optimization of FOWTs in complex marine environments, particularly under extreme wave conditions. Additionally, they contribute to the refinement of relevant numerical simulation methods.

CD22 is a critical inhibitory coreceptor predominantly expressed on the surface of B cells, playing a pivotal role in modulating B cell receptor (BCR) signaling and maintaining immune homeostasis. Its high B cell lineage specificity, rapid internalization capacity, and signal attenuation mediated by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) render it an ideal therapeutic target for B cell-related pathologies. In recent years, CD22-targeted therapeutic strategies have demonstrated significant clinical breakthroughs in the treatment of hematological malignancies and autoimmune diseases. These strategies encompass immunotoxins, radioimmunoconjugates, antibody-drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy. Notably, while monotherapies have achieved high response rates, dual-targeting approaches (e.g., CD19/CD22 CAR-T) have further mitigated the risk of antigen escape and profoundly enhanced long-term durable efficacy. This review systematically summarizes the molecular mechanisms of CD22 and the latest clinical advancements in its targeted therapies. Furthermore, we highlight the promising translational potential of CD22-targeted strategies-particularly CAR-T cell therapy-from oncology to the management of autoimmune disorders, outlining future research priorities within this rapidly evolving field.

N 6 -methyladenosine (m 6 A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3–METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239–580 of METTL3). We find that METTL3a is required for the METTL3–WTAP interaction, RNA m 6 A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3–METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m 6 A sequencing data shows that depletion of METTL3a globally disrupts m 6 A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m 6 A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a–mTOR axis as a potential therapeutic target for breast cancer.

Autophagy classically functions to protect cells and organisms during stressful conditions by catabolizing intracellular components to maintain energy homeostasis. Lysosome-autophagosome fusion is a critical step in emptying degraded unwanted contents. However, the mechanism of autophagosome fusion with lysosomes is still not fully understood. Here, we report that DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) interacts with Vesicle Associated Membrane Protein 8 (VAMP8) to mediate the fusion of autophagosomes with lysosomes. This DRAM1-VAMP8 interaction is enhanced upon stimulation of autophagy. However, DRAM1 preferentially mediates the fusion between autophagosomes and lysosomes by enhancing the assembly of the STX17-SNAP29-VAMP8 complex. Moreover, we reveal that DRAM1 specifically promotes the stability of lysosomal VAMP8 via inhibiting VAMP8 degradation by CHIP mediating ubiquitination. We also identify that DRAM1 inhibits the ubiquitination of VAMP8 at Lys 68,72, and 75 via competitively binding with CHIP. Furthermore, we demonstrate that DRAM1 promotes the extravasation of Hepatocellular Carcinoma (HCC) cells, and this process relies on enhanced autophagosome degradation. Our study reveals a mechanism for regulating autolysosome formation by DRAM1-VAMP8 association and suggests a potential strategy to inhibit the extravasation of HCC. DNA Damage Regulated Autophagy Modulator 1 (DRAM1) plays pivotal roles in autophagy regulation. Here, the authors show that DRAM1 stabilizes lysosomal VAMP8, thereby promoting autolysosome maturation. Furthermore, they establish that DRAM1–VAMP8 axis enhances autophagic flux and facilitates hepatocellular carcinoma extravasation, as validated in both zebrafish xenograft and mouse metastatic models.

Introduction Atrial fibrillation (AF) is self-limiting condition, but it may also increase the risk of stroke and death. The association between AF and surgery with stroke was assessed both subjectively and statistically using systematic review and meta-analysis. Methods For data collection, a thorough search was made in PubMed, EMBASE, Science Direct, Google Scholar, and Cochrane Library using searching keywords “postoperative ischemic stroke, atrial fibrillation, stroke, cardiac surgery, brain ischemia, and heart surgery”. Direct and indirect comparisons were made using random-effect network meta-analysis. Results 16-studies were identified comprising of 132,208 patient, 64% male, median age > 63 years and follow-up > 1.5 years. Pooling the results from the random-effects model showed odds ratios associated with the risk of stroke of surgical processes (CABG) in patients with AF. The odds ratio OR = 1.1 (0.65–1.54, P  < 0.001) and heterogeneity (I2 = 17%, P  = 0.13) exposing higher risk of the stroke. Odds ratio (HR 1.5, 0.9–1.71) without heterogeneity showed greater risk of stroke after heart valve surgery in patients with AF. Study 8 didn’t show any risk of the stroke after left atrial appendage (LAA) clipping intervention, but the outcomes were biased. A pooled analysis showed odd ratio OR, 2 (1.7–2.1, P  < 0.0001), without heterogeneity indicating higher stroke risk in general cardiac surgery. The patients undergone cardiac surgery from three studies with pooled analysis study-5 OR 2 (1.7–2.1, P  > 0.001), study-6 OR 1.8 (1.7–1.9, P  > 0.001), and study-14 OR 7.8 (6.2–8.1, P  > 0.0001). Conclusion The study clearly defines stroke outcomes when they are quantified, however, further research is required.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with drug resistance representing the primary barrier to effective treatment. Current research has largely focused on individual signaling pathways or isolated organelle functions, yet a comprehensive understanding of how these subcellular structures coordinate to drive resistance remains lacking. This review synthesizes current knowledge through the perspective of subcellular structural homeostasis, the dynamic balance maintained by intracellular organelles. We examine how key subcellular structures, the cell membrane, mitochondria, endoplasmic reticulum, ribosomes, lysosomes, exosomes, and stress granules, undergo functional remodeling to promote drug resistance. It is crucial that these organelles do not work independently but form an integrated and dynamic communication network. Mitochondria serve as the intracellular signaling hub, integrating calcium signals, metabolic progress, and stress responses, while exosomes function as intercellular messengers that spread the anti-drug-resistant phenotype between cells. This framework reveals why targeting individual structures often fails and highlights the therapeutic potential of disrupting inter-organelle communication. We discuss emerging clinical strategies targeting subcellular structures and identify critical knowledge gaps, including the need for non-invasive biomarkers and combination approaches that target multiple network nodes. By shifting the focus from isolated organelles to their coordinated interplay, this review offers a new paradigm for overcoming drug resistance in PDAC.

Mitochondria are crucial for a wide range of cellular processes. One of the most important is innate immunity regulation. Apart from functioning as a signaling hub in immune reactions, mitochondrial nucleic acids can themselves act as damage-associated molecular patterns (DAMPs) to participate in immune processes directly. This review synthesizes the current understanding of mitochondrial RNA (mtRNA) biology and its link to immune activation through aberrant accumulation. We focus on its origin through bidirectional mitochondrial transcription and metabolism, encompassing maturation (cleavage, polyadenylation, modification) and degradation. Dysregulation of mtRNA metabolism leads to mt-dsRNA (mitochondrial double-stranded RNA) accumulation, which escapes mitochondria via specific channels into the cytosol and serves as DAMPs to trigger an immune response. We discuss the critical roles of key regulatory factors, including PNPT1 (PNPase, Polyribonucleotide Nucleotidyltrans ferase 1), in controlling mt-dsRNA levels and preventing inappropriate immune activation. Finally, we review the implications of mt-dsRNA-driven inflammation in human diseases, including autoimmune disorders, cellular senescence, and viral infection pathologies, highlighting unresolved questions regarding mt-dsRNA release mechanisms.