bims-miptne 2026-01-04 papers

Biomedicines. 2025 Dec 18. pii: 3125. [Epub ahead of print]13(12):

Propofol-Induced Mitochondrial Dysfunction Is Independent of Mitochondrial Permeability Transition.

Aya Kawachi, Shoichiro Shibata, Eskil Elmér, Hiroyuki Uchino.

Background/Objectives: In recent years, it has been suggested that sedatives may cause brain damage. One possible mechanism is interference with oxidative phosphorylation of brain mitochondria, but much remains unknown. In this study, we focused on dexmedetomidine, midazolam, and propofol, essential sedatives in anesthesia and intensive care, and aimed to understand the effects of these drugs on mouse brain mitochondria. Methods: We measured changes in mitochondrial respiratory capacity and swelling rate upon exposure to these sedatives in a wide concentration range. For the sedative that demonstrated impaired mitochondrial function we explored the possible involvement of mitochondrial permeability transition pore opening using brain mitochondria from cyclophilin D knockout (CypD KO) mice and detected cytochrome c (cyt c) release by Western blot. Results: Of the three sedatives, only high concentrations of propofol exhibited reduced respiratory capacity and mitochondrial swelling, toxicity which was not prevented by CypD KO. Furthermore, propofol did not induce cyt c release. Conclusions: These results suggest that propofol-induced brain mitochondrial dysfunction is a mechanism independent of mPTP opening.

Keywords: cyclophilin D; mitochondrial dysfunction; mitochondrial permeability transition pore; mitochondrial respiratory capacity; mitochondrial swelling; propofol

DOI: https://doi.org/10.3390/biomedicines13123125

Biochem Biophys Res Commun. 2025 Dec 23. pii: S0006-291X(25)01900-X. [Epub ahead of print]797 153184

TGF-β1-induced downregulation of the mitochondrial Ca2+ uniporter facilitates the migration of hepatic stellate cells.

Naoki Kawata, Rubii Kondo, Yoshiaki Suzuki, Hisao Yamamura.

Transforming growth factor-β1 (TGF-β1) is a key profibrogenic cytokine that activates hepatic stellate cells (HSCs) and promotes their migration; however, its influence on mitochondrial Ca2+ regulation remains unclear. The mitochondrial Ca2+ uniporter (MCU) is essential for mitochondrial Ca2+ uptake and intracellular Ca2+ homeostasis, but its involvement in HSC activation has not been fully elucidated. Here, we investigated whether TGF-β1 modulates MCU expression and Ca2+ dynamics in HSCs. In LX-2 cells, TGF-β1 markedly reduced MCU mRNA and protein levels, and this repression was completely prevented by the ALK5 inhibitor SB431542. Both TGF-β1 treatment and MCU knockdown diminished mitochondrial Ca2+ uptake while increasing cytosolic Ca2+ responses to angiotensin II, and each intervention significantly enhanced HSC migration. These stimuli also increased CREB phosphorylation. Moreover, the CaMKII inhibitor KN-93, but not its inactive analog KN-92, suppressed HSC migration. Together, these findings indicate that TGF-β1-induced downregulation of MCU reshapes Ca2+ dynamics and promotes HSC migration, consistent with the involvement of CaMK-dependent signaling. This study demonstrates that TGF-β1 suppresses MCU expression, revealing a previously unrecognized link between a profibrogenic cytokine and mitochondrial Ca2+ regulation. Furthermore, our results show that MCU loss enhances migration in non-malignant HSCs, extending observations that were previously limited to cancer cells.

Keywords: Calcium signaling; Hepatic stellate cell; Migration; Mitochondrial calcium uniporter; TGF-β1

DOI: https://doi.org/10.1016/j.bbrc.2025.153184

Mol Cell Biol. 2026 Jan 02. 1-19

Mitochondria and Lipids in Cellular Signaling of the Brain: from Physiology to Neurodegeneration.

Plamena R Angelova, Lauren Millichap, Andrey Y Abramov.

The brain is one of the most lipid-rich organs, reflecting the critical role of lipid metabolism in neuronal and glial cell function. While mitochondria are central to energy metabolism, calcium signaling, and cell death, they do not utilize lipid oxidation for energy but rely on lipids for membrane integrity and intracellular communication. Here we review the interactions between lipids and mitochondria in intracellular signaling within brain cells, examining their roles in normal physiology and the mechanisms underlying major neurodegenerative diseases. Alterations in lipid homeostasis and mitochondrial metabolism are implicated in neurodegeneration, highlighting the importance of lipid-mediated mitochondrial signaling pathways. Understanding these interactions provides insights into cellular dysfunction in neurodegenerative disorders and may inform future therapeutic strategies targeting lipid and mitochondrial pathways.

Keywords: Lipid signaling; calcium signaling; lipid peroxidation; mitochondria; neurodegeneration

DOI: https://doi.org/10.1080/10985549.2025.2607428

Free Radic Biol Med. 2025 Dec 31. pii: S0891-5849(25)01472-8. [Epub ahead of print]

HPCAL1-BNIP3 axis promotes mitophagy-ferroptosis feedback loop that exacerbates intestinal ischemia-reperfusion injury.

Ximeng Ren, Xiaolong Lu, Yao Song, Meng Li, Tianyu Shao, Meihan Guo, Yang Liu, Dapeng Ding.

BACKGROUND: Intestinal ischemia and reperfusion (I/R) injury is a critical pathological condition characterized by the complex interactions among various cell death mechanisms. This study aims to systematically elucidate the regulatory interplay between ferroptosis and mitophagy in intestinal I/R injury, particularly highlighting the pivotal role of the neuronal calcium-binding protein HPCAL1.
METHODS: Using a mouse intestinal ischemia-reperfusion (I/R) model and a rat small intestinal epithelial cell (IEC-6) hypoxia/reoxygenation (H/R) model, we performed histopathological analysis; Western blotting; co-immunoprecipitation; qPCR; fluorescent probe-based detection; assays for reactive oxygen species and lipid peroxidation; and assessments of mitochondrial membrane potential and autophagic flux. Using these techniques, we examined the time course and features of injury and ferroptosis, mitochondrial dysfunction, and associated molecular regulatory mechanisms.
RESULTS: The study demonstrated that intestinal ischemia-reperfusion (I/R) injury is significantly time-dependent, peaking at 60 minutes of reperfusion in vivo or 3 hours of reoxygenation in vitro. Key ferroptosis indicators, including increased ACSL4, decreased GPX4 and XCT, GSH depletion, and Fe2+ accumulation, were markedly altered at this peak. Mitophagy inhibition alleviated tissue injury and ferroptosis, indicating excessive mitophagy activation is detrimental. Mechanistically, HPCAL1 was highly expressed at the injury peak. It bound to the mitophagy receptor BNIP3 in a calcium-dependent manner, enhancing BNIP3's stability and interaction with LC3-II, thereby excessively activating mitophagy. This process promoted ferroptosis via a burst of reactive oxygen species (ROS), independent of GPX4 expression changes. Concurrently, the ROS burst activated an Nrf2-mediated compensatory antioxidant response. Disrupting HPCAL1 or BNIP3 effectively broke this cycle, improving cell survival and mitochondrial function.
CONCLUSION: This study identifies a Ca2+ -mediated HPCAL1-BNIP3 signaling pathway that promotes ferroptosis through ROS-dependent mitophagy activation. It offers novel insights into the mechanisms underlying intestinal ischemia-reperfusion injury and supports the development of therapeutic strategies targeting the critical time window of injury progression as well as specific molecular targets.

Keywords: BNIP3; Ferroptosis; HPCAL1; Intestinal Ischemia-Reperfusion Injury; Mitophagy; Reactive Oxygen Species

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.12.054

Cell Death Dis. 2025 Dec 27.

Organelles and cancer cell pyroptosis: overview and perspectives.

AnPeng Qiu, JunDa Lin, HaoRan Hu, ZiHou Zhao, XinTong Cai, Yuyue Zhao, GuangTao Yu.

Pyroptosis, a gasdermin (GSDM)-mediated immunogenic programmed cell death modality, manifests through characteristic membrane permeabilization and proinflammatory cytokine release. Pyroptosis exhibits dual therapeutic advantages by remodeling the tumor microenvironment and potentiating systemic anti-tumor immunity, positioning it as a pivotal focus in cancer immunotherapy. However, researchers still focus current pyroptosis induction strategies predominantly on single molecular targets and have not sufficiently analyzed the inter-organelle communication networks that govern pyroptotic signaling cascades. This review provides a systematic exploration of organelle-specific ultrastructural alterations during pyroptosis progression and the molecular machinery regulating organelle-mediated pyroptotic pathways. We synthesize recent advances in organelle-targeted pyroptosis induction strategies, elucidating how inter-organelle crosstalk networks to enhance therapeutic efficacy. We aim to provide translational approaches for optimizing cancer treatment paradigms.

DOI: https://doi.org/10.1038/s41419-025-08371-9