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NF-κB/TOM6/PINK1-mediated mitophagy attenuates vascular calcification: Luteolin as a therapeutic modulator
Jinhe Li1, Qingchun Liang2, Yining Li3
1Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, China.
Abstract:
Vascular calcification (VC), a significant contributor to cardiovascular risk, lacks effective therapies. The natural flavonoid luteolin (LU) shows therapeutic potential, but its mechanism against VC is not fully elucidated. This study identifies a novel pathway wherein LU attenuates VC by restoring mitophagy via the Nuclear Factor Kappa B (NF-κB)/Translocase of Outer Mitochondrial Membrane 6 (TOM6)/PTEN-induced kinase 1 (PINK1) pathway. In vitro, LU dose-dependently inhibited calcification in vascular smooth muscle cells (VSMCs) and arterial rings, suppressing expression of osteogenic markers such as bone morphogenetic protein 2 (BMP2), Runt-related transcription factor 2 (Runx2), and restoring expression of contractile proteins such as alpha-smooth muscle actin (α-SMA), smooth muscle protein 22-alpha (SM22). In vivo, LU ameliorated VC in Vitamin D3 (VitD3)-overloaded mice and rats with chronic kidney disease (CKD). RNA sequencing identified TOM6 as a key gene upregulated during calcification and suppressed by LU. Functionally, TOM6 knockdown attenuated VC, whereas its overexpression exacerbated VC and reversed the anti-calcific effect of LU. Mechanistically, LU enhanced PINK1/Parkin-mediated mitophagy by downregulating TOM6, thereby improving mitochondrial bioenergetics. Furthermore, LU directly binds the inhibitor of nuclear factor kappa-B kinase subunits alpha and beta (IKKα/IKKβ), thereby inhibiting NF-κB nuclear translocation and TOM6 transcription. Collectively, our results identify the NF-κB/TOM6/PINK1 mitophagy axis as a key mechanistic pathway required for LU to mitigate VC, suggesting a novel therapeutic target.
Insights
The natural compound luteolin (LU) combats vascular calcification (VC) by restoring mitochondrial quality control through the NF-κB/TOM6/PINK1 mitophagy pathway. This finding suggests LU as a potential therapeutic for cardiovascular risk.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Vascular calcification (VC) significantly increases cardiovascular risk but lacks effective treatments.
- The therapeutic potential of the flavonoid luteolin (LU) for VC is recognized, yet its precise mechanism remains unclear.
- Understanding the molecular pathways underlying VC is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To elucidate the novel molecular mechanism by which luteolin (LU) attenuates vascular calcification (VC).
- To investigate the role of the Nuclear Factor Kappa B (NF-κB)/Translocase of Outer Mitochondrial Membrane 6 (TOM6)/PTEN-induced kinase 1 (PINK1) mitophagy pathway in LU's anti-calcific effects.
- To evaluate the therapeutic efficacy of LU in preclinical models of VC.
Main Methods:
- In vitro studies using vascular smooth muscle cells (VSMCs) and arterial rings treated with LU.
- In vivo experiments in Vitamin D3-overloaded mice and rats with chronic kidney disease (CKD).
- RNA sequencing to identify key genes involved in calcification and LU's effects, followed by functional knockdown and overexpression studies.
- Analysis of mitophagy, mitochondrial bioenergetics, and NF-κB signaling pathway activation.
Main Results:
- Luteolin (LU) dose-dependently inhibited calcification in vitro, suppressed osteogenic markers (BMP2, Runx2), and restored contractile proteins (α-SMA, SM22).
- LU ameliorated VC in vivo in mouse and rat models.
- RNA sequencing identified TOM6 as upregulated in VC and downregulated by LU; TOM6 modulation affected VC, and LU enhanced PINK1/Parkin-mediated mitophagy by downregulating TOM6.
- LU inhibited NF-κB activation by binding IKKα/IKKβ, reducing TOM6 transcription and improving mitochondrial function.
Conclusions:
- The study identifies a novel NF-κB/TOM6/PINK1 mitophagy axis as the key mechanism through which luteolin (LU) mitigates vascular calcification (VC).
- LU restores mitophagy and improves mitochondrial bioenergetics, offering a potential therapeutic strategy for VC.
- Targeting the NF-κB/TOM6/PINK1 mitophagy pathway presents a promising avenue for developing new treatments for vascular calcification.
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