Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension.

Area of Science:

• Cardiovascular Research
• Cell Biology
• Mitochondrial Biology

Background:

• Pulmonary hypertension (PH) involves endothelial dysfunction, but its underlying causes are not fully understood.
• The role of the hypoxia-inducible FUNDC1 (FUN14 domain-containing 1)-dependent mitophagy pathway in PH pathogenesis requires investigation.

Purpose of the Study:

• To investigate if the FUNDC1-dependent mitophagy pathway is involved in the development and progression of pulmonary hypertension.
• To elucidate the molecular mechanisms by which FUNDC1 influences endothelial cell function in the context of PH.

Main Methods:

• Analyzed FUNDC1 protein levels in human and animal PH samples.
• Utilized rodent PH models with global and endothelial-specific Fundc1 loss/gain-of-function.
• Performed histological, metabolic, and transcriptomic analyses, validated by HIF2α deficiency and pharmacological interventions.

Main Results:

• Reduced FUNDC1 levels were observed in PH lungs; Fundc1 deficiency exacerbated PH, while overexpression was protective.
• Endothelial FUNDC1 loss induced spontaneous PH, while augmentation protected against it.
• FUNDC1 deficiency led to impaired mitophagy, mitochondrial dysfunction, metabolic reprogramming, senescence, and increased IGFBP2 secretion, driving vascular remodeling.

Conclusions:

• FUNDC1-mediated mitophagy is essential for endothelial homeostasis and PH pathogenesis.
• Disruption of this pathway leads to PH, with observed changes in FUNDC1 and IGFBP2 relevant to human patients.
• Targeting endothelial mitophagy, pseudohypoxia, senescence, or IGFBP2 presents novel therapeutic avenues for PH.