TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

Xiucui Ma; David R Rawnsley; Attila Kovacs; Moydul Islam; John T Murphy; Chen Zhao; Minu Kumari; Layla Foroughi; Haiyan Liu; Kevin Qi; Aaradhya Diwan; Krzysztof Hyrc; Sarah Evans; Takashi Satoh; Brent A French; Kenneth B Margulies; Ali Javaheri; Babak Razani; Douglas L Mann; Kartik Mani; Abhinav Diwan

doi:10.1016/j.jacbts.2021.12.002

TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

JACC Basic Transl Sci. 2021 Dec 17;7(3):223-243. doi: 10.1016/j.jacbts.2021.12.002. eCollection 2022 Mar.

Authors

Xiucui Ma^{1

2}, David R Rawnsley¹, Attila Kovacs¹, Moydul Islam¹, John T Murphy^{1

2}, Chen Zhao¹, Minu Kumari¹, Layla Foroughi^{1

2}, Haiyan Liu^{1

2}, Kevin Qi¹, Aaradhya Diwan¹, Krzysztof Hyrc^{3

4}, Sarah Evans¹, Takashi Satoh⁵, Brent A French⁶, Kenneth B Margulies⁷, Ali Javaheri¹, Babak Razani^{1

2}, Douglas L Mann^{1

2

8}, Kartik Mani^{1

2}, Abhinav Diwan^{1

2

4

8

9}

Affiliations

¹ Center for Cardiovascular Research and Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
² John Cochran VA Medical Center, St. Louis, Missouri, USA.
³ Alafi Neuroimaging Laboratory, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴ Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
⁵ Department of Immune Regulation, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
⁶ Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
⁷ Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁹ Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA.

Abstract

Mitochondria are essential for cardiac myocyte function, but damaged mitochondria trigger cardiac myocyte death. Although mitophagy, a lysosomal degradative pathway to remove damaged mitochondria, is robustly active in cardiac myocytes in the unstressed heart, its mechanisms and physiological role remain poorly defined. We discovered a critical role for TRAF2, an innate immunity effector protein with E3 ubiquitin ligase activity, in facilitating physiological cardiac myocyte mitophagy in the adult heart, to prevent inflammation and cell death, and maintain myocardial homeostasis.

Keywords: AAV9, adeno-associated virus serotype 9; ER, endoplasmic reticulum; FS, fractional shortening; GFP, green fluorescent protein; IP, intraperitoneal; LV, left ventricular; MAM, mitochondria-associated membranes; MCM, MerCreMer; MEF, murine embryonic fibroblast; PINK1, PTEN-induced kinase 1; RFP, red fluorescent protein; TLR9, toll-like receptor 9; TRAF2; TRAF2, tumor necrosis factor receptor-associated factor-2; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; cTnT, cardiac troponin T; cell death; inflammation; mitophagy.

Abstract

Grants and funding