Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy

Autor: Yi Zhu, Xue-Jiao Sun, Xi-Qiong Han, Rui Yang, Naifeng Liu, Wen-Qi Ma
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Cancer Research
Clinical Biochemistry
Bone Morphogenetic Protein 2
Pharmaceutical Science
Core Binding Factor Alpha 1 Subunit
Mitochondrion
Mitochondrial Dynamics
0302 clinical medicine
Mitochondrial Precursor Protein Import Complex Proteins
Mitophagy
Nuclear Receptor Subfamily 4
Group A
Member 1
RNA
Small Interfering
Aorta
Cholecalciferol
Gene knockdown
medicine.diagnostic_test
Chemistry
Cell biology
030220 oncology & carcinogenesis
Mitochondrial fission
Signal Transduction
Dynamins
Nicotine
Receptors
Cell Surface
Diet
High-Fat
Streptozocin
Diabetes Mellitus
Experimental
Mitochondrial Proteins
03 medical and health sciences
Organ Culture Techniques
Western blot
medicine
Animals
Lactic Acid
Rats
Wistar
Vascular Calcification
Pharmacology
Biochemistry (medical)
Autophagy
Membrane Proteins
Membrane Transport Proteins
Cell Biology
medicine.disease
Rats
030104 developmental biology
Gene Expression Regulation
Apoptosis
Tumor Suppressor Protein p53
Calcification
Zdroj: Apoptosis. 25:321-340
ISSN: 1573-675X
1360-8185
DOI: 10.1007/s10495-020-01592-7
Popis: Arterial media calcification is related to mitochondrial dysfunction. Protective mitophagy delays the progression of vascular calcification. We previously reported that lactate accelerates osteoblastic phenotype transition of VSMC through BNIP3-mediated mitophagy suppression. In this study, we investigated the specific links between lactate, mitochondrial homeostasis, and vascular calcification. Ex vivo, alizarin S red and von Kossa staining in addition to measurement of calcium content, RUNX2, and BMP-2 protein levels revealed that lactate accelerated arterial media calcification. We demonstrated that lactate induced mitochondrial fission and apoptosis in aortas, whereas mitophagy was suppressed. In VSMCs, lactate increased NR4A1 expression, leading to activation of DNA-PKcs and p53. Lactate induced Drp1 migration to the mitochondria and enhanced mitochondrial fission through NR4A1. Western blot analysis of LC3-II and p62 and mRFP-GFP-LC3 adenovirus detection showed that NR4A1 knockdown was involved in enhanced autophagy flux. Furthermore, NR4A1 inhibited BNIP3-related mitophagy, which was confirmed by TOMM20 and BNIP3 protein levels, and LC3-II co-localization with TOMM20. The excessive fission and deficient mitophagy damaged mitochondrial structure and impaired respiratory function, determined by mPTP opening rate, mitochondrial membrane potential, mitochondrial morphology under TEM, ATP production, and OCR, which was reversed by NR4A1 silencing. Mechanistically, lactate enhanced fission but halted mitophagy via activation of the NR4A1/DNA-PKcs/p53 pathway, evoking apoptosis, finally accelerating osteoblastic phenotype transition of VSMC and calcium deposition. This study suggests that the NR4A1/DNA-PKcs/p53 pathway is involved in the mechanism by which lactate accelerates vascular calcification, partly through excessive Drp-mediated mitochondrial fission and BNIP3-related mitophagy deficiency.
Databáze: OpenAIRE
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