PMID- 33711329
OWN - NLM
STAT- MEDLINE
DCOM- 20210923
LR  - 20240226
IS  - 1090-2422 (Electronic)
IS  - 0014-4827 (Linking)
VI  - 402
IP  - 1
DP  - 2021 May 1
TI  - Mitoferrin 2 deficiency prevents mitochondrial iron overload-induced endothelial 
      injury and alleviates atherosclerosis.
PG  - 112552
LID - S0014-4827(21)00083-5 [pii]
LID - 10.1016/j.yexcr.2021.112552 [doi]
AB  - Endothelial dysfunction is an early step in the development of atherosclerotic 
      cardiovascular disease. Iron overload can lead to excessive mitochondrial 
      reactive oxygen species (mtROS) production, resulting in mitochondrial 
      dysfunction and vascular endothelial cell (EC) damage. Mitoferrin 2 (Mfrn2) is an 
      iron transporter in the inner mitochondrial membrane. This study aimed to assess 
      whether Mfrn2 and mitochondrial iron overload were involved in atherosclerosis 
      progression and to explore the potential mechanism. We observed significant 
      upregulation of Mfrn2 in the arteries of high-fat diet (HFD)-fed Apolipoprotein 
      E(-/-) (ApoE(-/-)) mice and in TNF-alpha-induced mouse aortic endothelial cells 
      (MAECs). Mfrn2 gene silencing inhibited mitochondrial iron overload, stabilized 
      mitochondrial membrane potential and improved mitochondrial function in 
      TNF-alpha-induced MAECs. Vascular EC-specific knockdown of Mfrn2 in ApoE(-/-) mice 
      markedly decreased atherosclerotic lesion formation and the levels of ICAM-1 in 
      aortas and reduced monocyte infiltration into the vascular wall. Furthermore, 
      TNF-alpha increased the binding of 14-3-3 epsilon (epsilon) and Mfrn2, preventing Mfrn2 
      degradation and leading to mitochondrial iron overload in ECs, while 14-3-3epsilon 
      overexpression increased Mfrn2 stability by inhibiting its ubiquitination. 
      Together, our results reveal that Mfrn2 deficiency attenuates endothelial 
      dysfunction by decreasing iron levels within the mitochondria and mitochondrial 
      dysfunction. These findings may provide new insights into preventive and 
      therapeutic strategies against vascular endothelial dysfunction in 
      atherosclerotic disease.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Wang, Dongchen
AU  - Wang D
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China.
FAU - Ye, Peng
AU  - Ye P
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China.
FAU - Kong, Chaohua
AU  - Kong C
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China.
FAU - Chao, Yuelin
AU  - Chao Y
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China.
FAU - Yu, Wande
AU  - Yu W
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China.
FAU - Jiang, Xiaomin
AU  - Jiang X
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China.
FAU - Luo, Jie
AU  - Luo J
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China.
FAU - Gu, Yue
AU  - Gu Y
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China. Electronic address: guyue_jessica@163.com.
FAU - Chen, Shao-Liang
AU  - Chen SL
AD  - Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China. Electronic address: chmengx@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210309
PL  - United States
TA  - Exp Cell Res
JT  - Experimental cell research
JID - 0373226
RN  - 0 (14-3-3 Proteins)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Cation Transport Proteins)
RN  - 0 (Slc25a28 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Ywhae protein, mouse)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
SB  - IM
MH  - 14-3-3 Proteins/genetics
MH  - Animals
MH  - Apolipoproteins E/*genetics
MH  - Atherosclerosis/*genetics
MH  - Cation Transport Proteins/*genetics
MH  - Diet, High-Fat/adverse effects
MH  - Disease Models, Animal
MH  - Endothelium/injuries/metabolism/pathology
MH  - Humans
MH  - Intercellular Adhesion Molecule-1/genetics
MH  - Iron Overload/complications/*genetics/metabolism
MH  - Mice, Knockout
MH  - Mitochondria/*metabolism/pathology
MH  - Tumor Necrosis Factor-alpha/genetics
MH  - Mice
OTO - NOTNLM
OT  - Atherosclerosis
OT  - Iron overload
OT  - Mfrn2
OT  - Mitochondria
EDAT- 2021/03/13 06:00
MHDA- 2021/09/24 06:00
CRDT- 2021/03/12 20:12
PHST- 2020/12/30 00:00 [received]
PHST- 2021/02/27 00:00 [revised]
PHST- 2021/03/02 00:00 [accepted]
PHST- 2021/03/13 06:00 [pubmed]
PHST- 2021/09/24 06:00 [medline]
PHST- 2021/03/12 20:12 [entrez]
AID - S0014-4827(21)00083-5 [pii]
AID - 10.1016/j.yexcr.2021.112552 [doi]
PST - ppublish
SO  - Exp Cell Res. 2021 May 1;402(1):112552. doi: 10.1016/j.yexcr.2021.112552. Epub 
      2021 Mar 9.