A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart

José A. Nicolás-Ávila, Ana V. Lechuga-Vieco, Lorena Esteban-Martínez, María Sánchez-Díaz, Elena Díaz-García, Demetrio J. Santiago, Andrea Rubio-Ponce, Jackson Liang Yao Li, Akhila Balachander, Juan A. Quintana, Raquel Martínez-de-Mena, Beatriz Castejón-Vega, Andrés Pun-García, Paqui G. Través, Elena Bonzón-Kulichenko, Fernando García-Marqués, Lorena Cussó, Noelia A-González, Andrés González-Guerra, Marta Roche-MolinaSandra Martin-Salamanca, Georgiana Crainiciuc, Gabriela Guzmán, Jagoba Larrazabal, Elías Herrero-Galán, Jorge Alegre-Cebollada, Greg Lemke, Carla V. Rothlin, Luis Jesús Jimenez-Borreguero, Guillermo Reyes, Antonio Castrillo, Manuel Desco, Pura Muñoz-Cánoves, Borja Ibáñez, Miguel Torres, Lai Guan Ng, Silvia G. Priori, Héctor Bueno, Jesús Vázquez, Mario D. Cordero, Juan A. Bernal, José A. Enríquez, Andrés Hidalgo

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. Video Abstract: [Figure presented] A system of macrophages in the heart supports cardiomyocyte health by phagocytosing exopher particles ejected from cardiomyocytes that contain defective mitochondria, among other cellular contents.

Original languageEnglish
Pages (from-to)94-109.e23
JournalCell
Volume183
Issue number1
DOIs
Publication statusPublished - Oct 1 2020

Keywords

  • autophagy
  • heart
  • macrophage
  • mitochondria
  • phagocytosis
  • proteostasis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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