TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis

Abstract

Mitochondrial damage triggers cell death signaling with catastrophic consequences in long-lived and irreplaceable cells, such as cardiac myocytes. Sensing of leaked mitochondrial DNA upon mitochondrial damage is also a potent trigger of inflammation. Whether the innate immune response pathways monitor mitochondrial damage in mitochondria-rich cardiac myocytes to prevent inflammation and cell death, remains unknown. TRAF2, an adaptor protein downstream of innate immune receptors, localizes to the mitochondria in the unstressed heart, with increased mitochondrial targeting in cardiomyopathic human hearts and after cardiac ischemia-reperfusion injury in mice. Inducible cardiomyocyte-specific deletion of TRAF2 in young adult mice impairs mitophagy with rapid decline in mitochondrial quality, upregulates TLR9 expression in cardiac myocytes, and results in inflammation and cell death manifesting as a fulminant cardiomyopathy. Preventing TLR9-mediated mitochondrial DNA sensing and resultant inflammation provides a short-term reprieve from cardiomyopathy, but persistence of damaged mitochondria results in long-term recrudescence. Restoration of TRAF2, but not the E3 ubiquitin ligase deficient mutant improves mitochondrial quality and rescues cardiomyopathy to restore homeostasis. Thus, the innate immune response acts via TRAF2 as the first line of defense against mitochondrial damage by orchestrating homeostatic mitophagy to dampen myocardial inflammation and prevent cell death.

TRAF2 Mediates Physiological Mitophagy

“…Previous studies showed that TRAF2 mediates cytoprotective TNF receptor signaling in the heart during stress, and, that TRAF2, in concert with Parkin, mediates mitophagy in cardiomyocytes in response to stress. 3 By extending these findings, Ma et al 2 showed that the loss of TRAF2 function attenuated mitophagy at baseline in the adult heart, accompanied by accumulation of mitochondrial proteins and mitochondrial dysfunction. Furthermore, the loss of TRAF2 function led to stimulation of TLR9 and macrophage infiltration, apoptosis, and cardiac dysfunction, which suggested that endogenous TRAF2 protects the heart against TLR9-induced sterile infection by facilitating safe disposal of mitochondrial DNA through activation of mitophagy, even without stress.…”

“…In this issue of JACC: Basic to Translational Science , using conditional cardiac-specific TRAF2 knock-out (KO) mice, Ma et al 2 showed that TNF-receptor−associated factor 2 (TRAF2), a mitochondrially localized E3 ubiquitin ligase, mediates mitophagy, and therefore plays a protective role in the adult heart at baseline. Previous studies showed that TRAF2 mediates cytoprotective TNF receptor signaling in the heart during stress, and, that TRAF2, in concert with Parkin, mediates mitophagy in cardiomyocytes in response to stress.…”

“…Furthermore, the loss of TRAF2 function led to stimulation of TLR9 and macrophage infiltration, apoptosis, and cardiac dysfunction, which suggested that endogenous TRAF2 protects the heart against TLR9-induced sterile infection by facilitating safe disposal of mitochondrial DNA through activation of mitophagy, even without stress. 2 …”

“…The study by Ma et al 2 is highly significant for multiple reasons. To my knowledge, this is the first report that clearly shows the molecular mechanism that mediates mitophagy, namely, the involvement of TRAF2 in the adult heart at baseline.…”

“…Parkin promotes proteasomal degradation of TRAF2, and down-regulation of Parkin extends the half-life of TRAF2 in 293 and SH-SY5Y cells. 4 Ma et al 2 showed that the level of Parkin was not altered in TRAF2 KO mice. Although overexpression of Parkin can rescue the loss of mitophagy in TRAF2-deficient murine embryonic fibroblast cells, the insufficient upregulation of Parkin in the presence of TRAF2 down-regulation appears to explain the distinct cardiac phenotype in TRAF2 and Parkin KO mice.…”