Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Biological Chemistry  

Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis, where mitochondria generate heat instead of ATP. The thermogenesis occurs through the activity of uncoupling protein 1 (UCP1), which specifically resides in the mitochondrial inner membrane and dissipates the mitochondrial proton gradient upon activation by long-chain free fatty acids. Although UCP1-independent proton leak has been reported, the mechanism underlying UCP1-independent mitochondrial membrane depolarization remains largely unknown. Here, using primary brown adipocytes, we found that cold-mimicking stimulation induces mitochondrial membrane depolarization even under UCP1 KO and knockdown conditions. Furthermore, during cold-mimicking stimulation, palmitic acid shows the most prominent increase in a lipolysis-dependent manner. Notably, palmitic acid directly decreases mitochondrial membrane potential specifically in mitochondria isolated from BAT but not in those isolated from liver or brain. These findings suggest that palmitic acid contributes to mitochondrial depolarization in BAT, thereby contributing to UCP1-independent depolarization.

DOI： 10.1016/j.jbc.2026.111177

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Cardiovascular Research  

Septic cardiomyopathy, one manifestation of multiple organ dysfunction syndrome, is a challenging complication in sepsis, and cytopathic hypoxia has been proposed to have a key role in the pathophysiology of multiple organ dysfunction syndrome. However, the underlying mechanisms remain unknown. Here, we show that upregulation of hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes following lipopolysaccharide (LPS) treatment suppresses mitochondrial respiration via inducible nitric oxide synthase-dependent nitric oxide, leading to cytopathic hypoxia. Cardiac-specific heterozygous deletion of HIF-1α ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy. Mechanistically, nuclear factor-κB (NF-κB)-mediated upregulation of cyclooxygenase 2 (COX2) and secretory phospholipases A2 (sPLA2) enhances HIF-1α expression following LPS exposure, whereas their inhibition prevents LPS-induced HIF-1α upregulation, cytopathic hypoxia and contractile dysfunction. In addition, phospholipid metabolites (prostaglandins and lysophospholipids/free fatty acids, respectively) stabilize HIF-1α via protein kinase A activation. These findings highlight a crucial role of excessive HIF-1α, driven by LPS-enhanced phospholipid metabolism, in septic cardiomyopathy through induction of cytopathic hypoxia.

DOI： 10.1038/s44161-025-00687-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Biochemical and Biophysical Research Communications  

Platelet-activating factor receptor (PAFR) is involved in various physiological processes, including the immune system and inflammatory responses. In addition to PAF, several oxidized phospholipids have been shown to act as ligands for PAFR. We have previously developed a comprehensive analysis method for oxidized phospholipids, and in this study, we employed this method to test whether additional oxidized phospholipids can activate PAFR. From an oxidized phosphatidylcholine mixture, we identified that 1-palmitoyl-2-(4'-oxo-butanoyl)-sn-glycero-3-phosphocholine (POBPC) functions as a novel PAFR activator, using preparative HPLC and comprehensive LC-MS/MS analysis of fractionated oxidized phospholipids. Next, multiple assays confirmed that POBPC acts as a bona fide PAFR agonist. The H248W mutation of PAFR attenuated the response to POBPC. Finally, POBPC induced phosphorylation of extracellular signal-regulated kinase in mouse peritoneal macrophages, which endogenously express PAFR. Our findings provide valuable insight into the biological functions of oxidized phospholipids, advancing our understanding of their roles in cellular processes.

DOI： 10.1016/j.bbrc.2025.151858

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Communications  

Ferroptosis, a form of cell death instigated by iron-dependent lipid peroxidation reactions (LPO), is emerging as a promising therapeutic target for cancer. While the mechanisms governing LPO induction and suppression have gradually been unveiled, questions persist regarding the specific cellular location of LPO and the utilization of iron in driving cell death. A comprehensive understanding of these aspects holds significant potential for advancing therapeutic applications in disease management. Here, we show lysosomal LPO in the initiation of ferroptosis, leveraging the hidden abilities of fluorescent detection probes. Intra-lysosomal LPO triggers iron leakage, fostering cell-wide LPO by augmenting lysosomal membrane permeabilization (LMP). Conversely, cell lines with low susceptibility to ferroptosis do not exhibit LMP. This deficiency is rectified by the concurrent administration of chloroquine, leading to LMP induction and subsequent cell death. These findings underscore enhancing LMP induction efficacy as a strategic approach to surmount resistance to therapies in cancer.

DOI： 10.1038/s41467-025-58909-w

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