Mitoferrin 2 deficiency prevents mitochondrial iron overload-induced endothelial injury and alleviates atherosclerosis

• DOI: 10.1016/j.yexcr.2021.112552
• Publication Date: 2021-03-09T21:02:18Z
• Authors: Dongchen Wang; Peng Ye; Chaohua Kong; Yuelin Chao; Wande Yu; Xiaomin Jiang; Jie Luo; Yue Gu; Shao-Liang Chen
• Keywords: Mice, Knockout; 0303 health sciences; Iron Overload; Tumor Necrosis Factor-alpha; Atherosclerosis; Diet, High-Fat; Intercellular Adhesion Molecule-1; Mitochondria; 3. Good health; Disease Models, Animal; 03 medical and health sciences; Apolipoproteins E; 14-3-3 Proteins; Animals; Humans; Endothelium; Cation Transport Proteins

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-α-induced mouse aortic endothelial cells (MAECs). Mfrn2 gene silencing inhibited mitochondrial iron overload, stabilized mitochondrial membrane potential and improved mitochondrial function in TNF-α-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-α increased the binding of 14-3-3 epsilon (ε) and Mfrn2, preventing Mfrn2 degradation and leading to mitochondrial iron overload in ECs, while 14-3-3ε 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.