PMID- 25339503
OWN - NLM
STAT- MEDLINE
DCOM- 20150317
LR  - 20230815
IS  - 1941-3297 (Electronic)
IS  - 1941-3289 (Print)
IS  - 1941-3289 (Linking)
VI  - 8
IP  - 1
DP  - 2015 Jan
TI  - Tumor necrosis factor receptor-associated factor 2 mediates mitochondrial 
      autophagy.
PG  - 175-87
LID - 10.1161/CIRCHEARTFAILURE.114.001635 [doi]
AB  - BACKGROUND: Tumor necrosis factor (TNF) signaling protects against 
      ischemia/reperfusion-induced cardiomyocyte death, in vitro, ex vivo, and in vivo. 
      TNF-receptor-associated factor 2 (TRAF2), an E3 ubiquitin ligase, coordinates 
      cytoprotective signaling downstream of both TNF receptors, via unclear 
      mechanisms. Noting that TRAF2 is recruited to mitochondria, and that autophagic 
      removal of ubiquitin-tagged damaged mitochondria is cytoprotective, we tested the 
      hypothesis that TRAF2 mediates mitochondrial autophagy. METHODS AND RESULTS: 
      TRAF2 localizes to the mitochondria in neonatal rat cardiac myocytes, and TNF 
      treatment transcriptionally upregulates TRAF2 abundance in the mitochondrial 
      subfraction. TRAF2 colocalizes with ubiquitin, p62 adaptor protein, and 
      mitochondria within LC3-bound autophagosomes; and exogenous TRAF2 enhances 
      autophagic removal of mitochondria. TRAF2 knockdown with adenoviral shRNA 
      transduction induces accumulation of depolarized mitochondria in resting neonatal 
      rat cardiac myocytes, as well as in those treated with TNF or uncoupling agent 
      carbonyl cyanide m-chlorophenyl hydrazone, suggesting an essential role for TRAF2 
      in homeostatic and stress-induced mitochondrial autophagy. TRAF2 also colocalizes 
      and interacts with PARKIN, a previously described E3 ubiquitin ligase and 
      mitophagy effector, on depolarized mitochondria in neonatal rat cardiac myocytes. 
      Exogenous expression of TRAF2, but not its E3 ligase-deficient mutants, is 
      sufficient to partially restore mitophagy in the setting of PARKIN knockdown, 
      suggesting redundancy in their ubiquitin ligase roles. TRAF2 abundance increases 
      in the mitochondrial subfraction of ischemia/reperfusion-modeled hearts; and 
      exogenous TRAF2, but not its E3 ligase-deficient mutants, reduces depolarized 
      mitochondria and rescues cell death in neonatal rat cardiac myocytes subjected to 
      hypoxia/reoxygenation. CONCLUSIONS: Taken together, these data indicate an 
      essential role for TRAF2 in concert with PARKIN as a mitophagy effector, which 
      contributes to TRAF2-induced cytoprotective signaling.
CI  - (c) 2014 American Heart Association, Inc.
FAU - Yang, Kai-Chun
AU  - Yang KC
AD  - From 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.).
FAU - Ma, Xiucui
AU  - Ma X
AD  - From 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.).
FAU - Liu, Haiyan
AU  - Liu H
AD  - From 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.).
FAU - Murphy, John
AU  - Murphy J
AD  - From 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.).
FAU - Barger, Philip M
AU  - Barger PM
AD  - From 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.).
FAU - Mann, Douglas L
AU  - Mann DL
AD  - From 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.).
FAU - Diwan, Abhinav
AU  - Diwan A
AD  - From 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.). 
      adiwan@dom.wustl.edu.
LA  - eng
GR  - HL58081/HL/NHLBI NIH HHS/United States
GR  - HL107594/HL/NHLBI NIH HHS/United States
GR  - I01 BX001969/BX/BLRD VA/United States
GR  - R01 HL107594/HL/NHLBI NIH HHS/United States
GR  - HL89543/HL/NHLBI NIH HHS/United States
GR  - 111094/PHS HHS/United States
GR  - R01 HL111094/HL/NHLBI NIH HHS/United States
GR  - I01 BX000448/BX/BLRD VA/United States
GR  - R01 HL089543/HL/NHLBI NIH HHS/United States
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
GR  - R01 HL058081/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20141022
PL  - United States
TA  - Circ Heart Fail
JT  - Circulation. Heart failure
JID - 101479941
RN  - 0 (TNF Receptor-Associated Factor 2)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - *Autophagy
MH  - Disease Models, Animal
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria, Heart/*metabolism/pathology
MH  - Myocardial Reperfusion Injury/*metabolism/pathology
MH  - Myocytes, Cardiac/*metabolism/pathology
MH  - Rats
MH  - Signal Transduction
MH  - TNF Receptor-Associated Factor 2/*metabolism
PMC - PMC4303508
MID - NIHMS637458
OTO - NOTNLM
OT  - TNF receptor
OT  - TNF receptor-associated factor 2
OT  - mitochondrial degradation
EDAT- 2014/10/24 06:00
MHDA- 2015/03/18 06:00
PMCR- 2016/01/01
CRDT- 2014/10/24 06:00
PHST- 2014/10/24 06:00 [entrez]
PHST- 2014/10/24 06:00 [pubmed]
PHST- 2015/03/18 06:00 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - CIRCHEARTFAILURE.114.001635 [pii]
AID - 10.1161/CIRCHEARTFAILURE.114.001635 [doi]
PST - ppublish
SO  - Circ Heart Fail. 2015 Jan;8(1):175-87. doi: 10.1161/CIRCHEARTFAILURE.114.001635. 
      Epub 2014 Oct 22.