MFN2 alleviates mitochondrial calcium overload in sepsis-induced myopathy by modulating GRP75–VDAC1 interaction

IP3R drives cardiomyocyte injury by enhancing MAM-mediated Ca2+ transfer and mitochondrial dysfunction.

BACKGROUND Heart failure (HF) is the terminal stage of various cardiovascular diseases. Mitochondrial Ca2+ overload and dysfunction mediated by mitochondria-associated ER membranes (MAMs) are recognized contributors to HF pathogenesis; however, the underlying molecular mechanisms remain incompletely understood. METHODS An in vitro model of cardiomyocyte injury was established using angiotensin II (Ang II)-stimulated H9c2 cells. IP3R was knocked down using specific siRNA. Cell viability (CCK-8), apoptosis (Annexin V/TUNEL), and hypertrophy (phalloidin staining) were assessed. IP3R expression and mitochondrial complex subunits were analyzed by western blotting. MAM formation was examined by transmission electron microscopy and immunofluorescence co-localization. Mitochondrial function was evaluated by measuring ATP levels, ROS (MitoSOX), mitochondrial membrane potential (TMRM), and Ca2+ uptake (Rhod-2). RESULTS Ang II stimulation reduced cell viability, induced hypertrophy and apoptosis, and promoted MAM formation. Mechanistically, Ang II upregulated IP3R expression and enhanced MAM-mediated mitochondrial Ca2+ overload, leading to decreased mitochondrial membrane potential, elevated ROS, and reduced ATP production. Notably, genetic knockdown of IP3R attenuated these pathological changes, reducing MAM formation and mitochondrial Ca2+ overload while restoring mitochondrial function and cell viability. CONCLUSION Our findings suggest that IP3R may exacerbate cardiomyocyte injury by facilitating MAM-mediated Ca2+ transfer and mitochondrial dysfunction, indicating that targeting IP3R could represent a potential therapeutic strategy for HF. However, the upstream mechanisms of IP3R upregulation and the causal role of mitochondrial Ca2+ uptake require further investigation.

PGAM5-mediated VDAC1 oligomerization Facilitates Ponatinib-Induced Cardiotoxicity via Disrupting the Mitophagy-Mitochondrial unfolded protein response Synergistic Defense Crosstalk.

These findings identify the PGAM5/VDAC1 axis as a key mechanism linking ponatinib stress to coordinated failure of MQC in the heart and targeting PGAM5-dependent VDAC1 oligomerization may represent a potential strategy for limiting ponatinib-associated cardiotoxicity.

Formononetin Mitigates Age-Related Sarcopenia by Blocking Mitochondrial Ferroptosis via SIRT1/PGC-1α Signaling.

Results showed that FMN improved lean mass, grip strength, mitochondrial membrane potential, and ATP production, while reducing ROS and ferroptosis by regulating ACSL4, GPX4, and SLC7A11.

SREBF2 promotes mitophagy and protects against ferroptosis via Cav-1-regulated PINK1/Parkin signaling in ischemic heart failure

POU2F1 promotes hypertensive cardiac fibrosis by regulating mitochondrial homeostasis through PINK1/Parkin-dependent mitophagy

Hypertension-induced cardiac fibrosis is a major risk factor for heart failure; although disrupted mitochondrial homeostasis has been confirmed to serve a critical role in the pathological process, its upstream regulatory factors remain incompletely understood. In the current study, RNA sequencing and bioinformatics analyses identified POU domain class 2 transcription factor 1 (POU2F1) as a hub transcriptional regulator in the fibrotic cardiac tissues of spontaneously hypertensive rats (SHRs). The expression levels of POU2F1 were associated with the severity of myocardial fibrosis, and cardiac expression of PTEN-induced kinase 1 (PINK1) and Parkin in SHRs. Complementing these in vivo observations, angiotensin II stimulation significantly upregulated POU2F1 expression in cardiac fibroblasts (CFs) in vitro. Furthermore, POU2F1 expression exhibited a positive correlation with fibroblast activation, as indicated by α-smooth muscle actin fluorescence intensity. Mechanistically, POU2F1 knockdown attenuated CF activation, improved mitochondrial structure and energy metabolism, and restored PINK1/Parkin-mediated mitophagy balance in vivo and in vitro. Conversely, POU2F1 overexpression was associated with enhanced PINK1/Parkin-mediated mitophagy signaling. Crucially, through chromatin immunoprecipitation-quantitative PCR, electrophoretic mobility shift assay and dual-luciferase reporter assay, it was demonstrated that POU2F1 can directly bind to the PINK1 promoter to activate its transcription. In conclusion, the present study identified a novel role for POU2F1 in hypertensive cardiac fibrosis, demonstrating that it exacerbates disease progression by disrupting mitochondrial homeostasis through transcriptional activation of PINK1, accompanied by alterations consistent with enhanced PINK1/Parkin-mediated mitophagy.

ITCH‐Mediated Ubiquitination and Degradation of THBS1: A Key Mechanism for Enhancing Mitochondrial Biogenesis and Alleviating Mouse Skeletal Muscle Atrophy

ABSTRACT Aim Skeletal muscle atrophy is tightly associated with maladaptive alterations in mitochondrial function and morphology. Itchy E3 ubiquitin‐protein ligase (ITCH) modulates mitochondria, and thrombospondin 1 (THBS1) positively regulates muscle atrophy, but their roles in muscle atrophy are unclear. Methods A muscle atrophy model was established in C57BL/6 mice via daily intraperitoneal injection of dexamethasone (Dex, 20 mg/kg). ITCH overexpression in skeletal muscle was achieved by adeno‐associated virus serotype 9 injection. C2C12 cells were treated with 50 μM Dex to mimic in vitro muscle atrophy. Skeletal muscle atrophy in mice was evaluated using hematoxylin–eosin staining and immunofluorescence staining. Mitochondrial damage was assessed via transmission electron microscopy, succinate dehydrogenase staining, and JC‐1 staining. Immunoprecipitation‐liquid chromatography/mass spectrometry, molecular docking, and co‐immunoprecipitation were used to investigate the interaction between ITCH and THBS1. Phosphoproteomics analysis was performed to detect the THBS1 downstream proteins. Results Dex treatment downregulated ITCH expression in skeletal muscle. ITCH overexpression increased body weight, muscle mass, and muscle strength, downregulated the expression of atrophy‐related genes (Atrogin‐1, Mstn, MuRF‐1), and promoted mitochondrial biogenesis. The results of the C2C12 cells were consistent with those obtained in vivo. Proteomic profiling and Co‐IP confirmed ITCH–THBS1 interaction and subsequent THBS1 ubiquitination. THBS1 knockdown reduced the expression of Atrogin‐1 and MuRF‐1 and inhibited the phosphorylation of JUN and Map3k7, whereas THBS1 overexpression reversed the ITCH‐mediated improvement in mitochondrial biogenesis. Conclusion ITCH enhances mitochondrial biogenesis and mitigates Dex‐induced muscle atrophy by promoting the ubiquitin‐dependent degradation of THBS1 and subsequent inhibition of downstream JUN/Map3k7 phosphorylation.