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

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)

Abstract

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?

Original languageEnglish
Pages (from-to)331-345.e22
JournalCell
Volume171
Issue number2
DOIs
Publication statusPublished - Oct 5 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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