Tumor necrosis factor receptor-associated factor 2 mediates mitochondrial autophagy

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Kai-Chun Yang1, Xiucui Ma1, Haiyan Liu1

  • 1From the Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine (K.-C.Y., X.M., H.L., J.M., P.M.B., D.L.M., A.D.), Department of Cell Biology and Physiology (D.L.M., A.D.), Washington University School of Medicine, St. Louis, MO; and Department of Medicine, John Cochran VA Medical Center, St. Louis, MO (X.M., H.L., A.D.).

Circulation. Heart Failure
|October 24, 2014
PubMed
Abstract

Insights

Tumor necrosis factor-associated factor 2 (TRAF2) mediates mitochondrial autophagy, protecting heart cells from death. TRAF2 works with PARKIN to remove damaged mitochondria, crucial for cell survival during stress.

Area of Science:

  • Cardiovascular Biology
  • Cellular Stress Response
  • Mitochondrial Dynamics

Background:

  • Tumor necrosis factor (TNF) signaling protects cardiomyocytes from death during ischemia/reperfusion injury.
  • TNF-receptor-associated factor 2 (TRAF2) coordinates cytoprotective signaling downstream of TNF receptors through incompletely understood mechanisms.
  • TRAF2's mitochondrial localization and the cytoprotective role of autophagic removal of damaged mitochondria prompted investigation into TRAF2's role in mitochondrial autophagy (mitophagy).

Purpose of the Study:

  • To test the hypothesis that TRAF2 mediates mitochondrial autophagy.
  • To elucidate the role of TRAF2 in cardiomyocyte protection against stress-induced death.

Main Methods:

  • Investigated TRAF2 localization and abundance in mitochondria of neonatal rat cardiac myocytes.
  • Utilized adenoviral shRNA to knock down TRAF2 and assessed mitochondrial health and autophagy.
  • Examined TRAF2 interaction with PARKIN on depolarized mitochondria.
  • Assessed the impact of exogenous TRAF2 expression on mitophagy in PARKIN knockdown models.
  • Evaluated TRAF2's role in a rat model of cardiac ischemia/reperfusion injury.

Main Results:

  • TRAF2 localizes to mitochondria and its abundance increases with TNF treatment.
  • TRAF2 is found within autophagosomes with mitochondria and ubiquitin, and its presence enhances mitochondrial autophagy.
  • TRAF2 knockdown leads to accumulation of damaged mitochondria, indicating its essential role in mitochondrial quality control.
  • TRAF2 interacts with PARKIN on depolarized mitochondria, and TRAF2 can compensate for PARKIN loss in mitophagy.
  • TRAF2 abundance increases in hearts subjected to ischemia/reperfusion.
  • Exogenous TRAF2 protects against hypoxia/reoxygenation-induced cell death by reducing mitochondrial damage.

Conclusions:

  • TRAF2 plays an essential role in mitophagy as a key effector, acting in concert with PARKIN.
  • TRAF2-mediated mitophagy contributes significantly to TRAF2's cytoprotective signaling pathways.
  • These findings highlight TRAF2 as a critical component in maintaining mitochondrial homeostasis and preventing cardiac cell death.
Keywords:
TNF receptorTNF receptor–associated factor 2mitochondrial degradation

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