A network of macrophages supports mitochondrial homeostasis in the heart

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

A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart

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.This study was supported by Intramural grants from the Severo Ochoa program (IGP-SO); grants SAF2015-71878-REDT and SAF2014-56819-R from the Ministerio de Ciencia e Innovacion (MICINN) to A.C.; European Research Council grant EU-rhythmy (ERC-ADG-2014-ID:669387) to S.G.P., and MATRIX (ERC-COG-2018-ID: 819775) to B.I.; L.G.N. is supported by SIgN core funding from A∗STAR; grant BFU2016-75144-R from the Ministry of Science and Innovation to J.A.B,; grants PGC2018-096486-B-I00 and RD16/0011/0019 (ISCIII) from MICINN, TNE-17CVD04 from the Leducq Foundation, and S2017/BMD-3875 from the Comunidad de Madrid to M.T; intramural grant TPC/O-SO and grants SAF2015-65633-R, RTI2018-099357-B-I00, and HFSP (RGP0016/2018) to J.A.E.; intramural grant IGP-SO to J.A.-C. and A.H.; BIO2017-83640-P and RYC-2014-16604 to J.A-C; grants PRB3 (IPT17/0019-ISCIII-SGEFI/ERDF, ProteoRed) from the Carlos III Institute of Health and Fondo de Investigaciones Sanitarias, BIO2015-67580-P and PGC2018-097019-B-I00 from MICINN to J.V.; RTI2018-096068 from MICINN, AFM, MDA, LaCaixa-HR17-00040, UPGRADE-H2020-825825, and European Research Council (ERC-741538) to P.M.C.; S2017/BMD-3867 RENIM-CM from the Comunidad de Madrid and cofunded with European structural and investment funds to M.D.; 120/C/2015-20153032 from Fundació la Marató de TV3, SAF2015-65607-R and RTI2018-095497-B-I00 from MICINN, HR17_00527 from La Caixa Foundation, and TNE-18CVD04 from the Leducq Foundation to A.H.; C.V.R. is a Howard Hughes Medical Institute Faculty Scholar; J.A.N-A is supported by fellowship SVP-2014-068595, A.V.L.-V. by SVP-2013-068089, L.E.-M. by FJCI-2016-29384, and A.R.-P. by BES-2016-076635, all from MICINN; and the CNIC International Postdoctoral Program (EU grant agreement 600396 to D.J.S.). The CNIC is supported by the MICINN and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MICINN award SEV-2015-0505)