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

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Atherosclerosis Research

Background:

• Endothelial dysfunction is a key early event in atherosclerosis.
• Iron overload contributes to mitochondrial dysfunction and endothelial cell damage via increased mitochondrial reactive oxygen species (mtROS).
• Mitoferrin 2 (Mfrn2) is an inner mitochondrial membrane iron transporter implicated in cellular iron homeostasis.

Purpose of the Study:

• To investigate the role of Mfrn2 and mitochondrial iron overload in atherosclerosis progression.
• To elucidate the underlying mechanisms linking Mfrn2 to endothelial dysfunction.

Main Methods:

• Upregulation of Mfrn2 was assessed in high-fat diet-fed ApoE-/- mice and TNF-α-induced mouse aortic endothelial cells (MAECs).
• Mfrn2 gene silencing and vascular endothelial cell-specific knockdown were employed.
• Mitochondrial function, iron levels, and protein interactions (Mfrn2 and 14-3-3ε) were analyzed.

Main Results:

• Mfrn2 was significantly upregulated in atherosclerotic mouse arteries and TNF-α-treated MAECs.
• Mfrn2 silencing improved mitochondrial function and reduced iron overload in MAECs.
• EC-specific Mfrn2 knockdown in ApoE-/- mice decreased atherosclerotic lesions, ICAM-1 levels, and monocyte infiltration.
• TNF-α stabilized Mfrn2 by increasing binding with 14-3-3ε, inhibiting Mfrn2 degradation and promoting mitochondrial iron overload.

Conclusions:

• Mfrn2 deficiency attenuates endothelial dysfunction by reducing mitochondrial iron and improving mitochondrial function.
• The interaction between TNF-α, 14-3-3ε, and Mfrn2 plays a crucial role in mitochondrial iron overload and endothelial dysfunction.
• Targeting Mfrn2 presents a potential therapeutic strategy for preventing and treating vascular endothelial dysfunction in atherosclerotic diseases.