Biology subjects

Matoba, T.

Publications and source records attributed to Matoba, T..

3 recordsLinked to original sources

bioRxiv2024

Drp1-mediated mitochondrial fission protects macrophages from mtDNA/ZBP1-mediated sterile inflammation and inhibits post-infarct cardiac remodeling

BackgroundIschemic heart disease is a leading cause of death worldwide, and heart failure after myocardial infarction (MI) is a growing issue in this aging society. Macrophages play central roles in left ventricular (LV) remodeling after MI. Mitochondria consistently change their morphology, including fission and fusion, but the role of these mitochondrial morphological changes, especially in macrophages, is unknown. This study aims to illuminate the effects and mechanisms of Dynamin-related protein 1 (Drp1), a molecule mediating mitochondrial fission, in macrophages for cardiac remodeling after MI. MethodsThis study utilized genetically altered mice lacking Drp1 in monocytes/macrophages (Drp1-KO) to elucidate the specific role of macrophage Drp1 in post-infarct LV remodeling. ResultsDeletion of Drp1 in macrophages exacerbated LV remodeling, including reduced ejection fraction and increased LV diameters, which resulted in decreased survival after MI. Histological analysis indicated increased fibrosis and sustained macrophage accumulation in Drp1-KO mice. Blockade of Drp1 in macrophages decreased mitochondrial fission and impaired mitophagy, leading to the subsequent release of mitochondrial DNA (mtDNA) to the cytosol and induction of inflammatory cytokines. This induction was abrogated by an autophagy inducer, Tat-beclin1, or siRNA-mediated knockdown of Z-DNA Binding Protein 1 (ZBP1). Deletion of ZBP1 in bone marrow-derived cells abrogated LV remodeling induced by Drp1 inhibitor, Mdivi-1. ConclusionMacrophage Drp1 plays a critical role in the pathobiology of LV remodeling after MI, especially mitochondria quality control mechanisms. Macrophage Drp1 could be a novel therapeutic molecule to mitigate the progression of LV remodeling and consequent heart failure after MI.

biochemistry↗

bioRxiv2023

Cyclophilin D induces necrotic core formation by promoting mitochondria-mediated macrophage apoptosis in advanced atherosclerotic lesions

BackgroundIn advanced atherosclerotic lesions, apoptotic cell death of plaque macrophages results in necrotic core formation and plaque vulnerability. Cyclophilin D (CypD) is a mitochondria-specific cyclophilin involved in the process of cell death after organ ischemia-reperfusion. However, the role of CypD in atherosclerosis, especially in necrotic core formation, is unknown. MethodsTo clarify the specific role of CypD, apolipoprotein-E/CypD-double knockout (ApoE-/-CypD-/-) mice were generated. These mice were fed a high-fat diet containing 0.15% cholesterol for 24 weeks to accelerate atherosclerotic lesion development. ResultsThe deletion of CypD decreased the necrotic core size, accompanied by a reduction of macrophage apoptosis compared to control ApoE-/- mice. In RAW264.7 cells treated with endoplasmic reticulum stress inducer thapsigargin, the release of cytochrome c to the cytosol was attenuated by siRNA-mediated knockdown of CypD. Ly-6Chigh inflammatory monocytes in the peripheral blood leukocytes and mRNA expression of Il1b in the aorta were decreased by the deletion of CypD. In contrast, siRNA-mediated knockdown of CypD did not significantly decrease Il1b nor Ccl2 mRNA expression in RAW264.7 cells treated with LPS and IFN-{gamma}, suggesting that inhibition of inflammation in vivo is likely due to decreased cell death in the atherosclerotic lesions rather than a direct action of CypD deletion on the macrophage. ConclusionsThis is the first report showing that CypD induces macrophage death and promotes necrotic core formation in advanced atherosclerotic lesions. CypD could be a novel therapeutic target for treating atherosclerotic vascular diseases.

molecular biology↗

bioRxiv2021

Extracellular vesicles synchronize cellular phenotypes of differentiating cells

During embryonic development, cells differentiate in a coordinated manner, aligning their fate decisions and differentiation stages with those of surrounding cells. However, little is known about the mechanisms that regulate this synchrony. Here we show that cells in close proximity synchronize their differentiation stages and cellular phenotypes with each other via extracellular vesicle (EV)-mediated cellular communication. We previously established a mouse embryonic stem cell (ESC) line harboring an inducible constitutively active protein kinase A (CA-PKA) gene and found that the ESCs rapidly differentiated into mesoderm after PKA activation. In the present study, we performed a co-culture of control ESCs and PKA-ESCs, finding that both ESCs rapidly differentiated in synchrony even when PKA was activated only in PKA-ESCs, a phenomenon we named "Phenotypic Synchrony of Cells (PSyC)". We further demonstrated PSyC was mediated by EVs containing miR-132. PKA-ESC-derived EVs and miR-132-containing artificial nano-vesicles similarly enhanced mesoderm and cardiomyocyte differentiation in ESCs and ex vivo embryos, respectively. PSyC is a new form of cell-cell communication mediated by EV regulation of neighboring cells and could be broadly involved in tissue development and homeostasis.

cell biology↗