Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages

Ying Wang, Manikandan Subramanian, Arif Yurdagul, Valéria C. Barbosa-Lorenzi, Bishuang Cai, Jaime de Juan-Sanz, Timothy A. Ryan, Masatoshi Nomura, Frederick R. Maxfield, Ira Tabas

研究成果: Contribution to journalArticle査読

96 被引用数 (Scopus)

抄録

Clearance of apoptotic cells (ACs) by phagocytes (efferocytosis) prevents post-apoptotic necrosis and dampens inflammation. Defective efferocytosis drives important diseases, including atherosclerosis. For efficient efferocytosis, phagocytes must be able to internalize multiple ACs. We show here that uptake of multiple ACs by macrophages requires dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which is triggered by AC uptake. When mitochondrial fission is disabled, AC-induced increase in cytosolic calcium is blunted owing to mitochondrial calcium sequestration, and calcium-dependent phagosome formation around secondarily encountered ACs is impaired. These defects can be corrected by silencing the mitochondrial calcium uniporter (MCU). Mice lacking myeloid Drp1 showed defective efferocytosis and its pathologic consequences in the thymus after dexamethasone treatment and in advanced atherosclerotic lesions in fat-fed Ldlr−/− mice. Thus, mitochondrial fission in response to AC uptake is a critical process that enables macrophages to clear multiple ACs and to avoid the pathologic consequences of defective efferocytosis in vivo. How are dead cells in our bodies rapidly cleared by phagocytes in order to avoid inflammation and necrosis?

本文言語英語
ページ(範囲)331-345.e22
ジャーナルCell
171
2
DOI
出版ステータス出版済み - 10 5 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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