Format

Send to

Choose Destination
Cell. 2017 Oct 5;171(2):331-345.e22. doi: 10.1016/j.cell.2017.08.041. Epub 2017 Sep 21.

Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages.

Author information

1
Department of Medicine, Columbia University, New York, NY 10032, USA.
2
Department of Medicine, Columbia University, New York, NY 10032, USA; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India.
3
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
4
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
5
Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Physiology, Columbia University, New York, NY 10032, USA. Electronic address: iat1@columbia.edu.

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.

KEYWORDS:

DRP1; apoptotic cells; atherosclerosis; calcium signaling; efferocytosis; macrophage; mitochondrial dynamics; mitochondrial fission; phagocytosis

PMID:
28942921
PMCID:
PMC5679712
DOI:
10.1016/j.cell.2017.08.041
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center