Research progress on the mechanism and treatment of mitochondrial dysfunction in arterial medial calcification

doi:10.3877/cma.j.issn.2095-655X.2025.03.005

Abstract

Abstract:

Arterial calcification is a pathological process in which calcium salts abnormally deposit in the arterial wall. It can be classified into intimal calcification and medial calcification based on the lesion location. Among them, arterial medial calcification is common in patients with chronic kidney disease, diabetes, and the elderly, and is strongly associated with cardiovascular diseases. In recent years, the role of mitochondrial dysfunction in this process has attracted increasing attention. Mitochondria not only provide energy for cells but also participate in regulating oxidative stress and apoptosis. Their dysfunction can promote the transformation of vascular smooth muscle cells into an osteoblast-like phenotype and accelerate calcium salt deposition. The author mainly reviews the basic and clinical research progress of mitochondrial dysfunction in the pathogenesis of arterial middle calcification in recent years, in order to further provide new ideas for clinical prevention and treatment of arterial calcification.

Key words: Arterial medial calcification, Mitochondrial dysfunction, Vascular smooth muscle cells, Oxidative stress, Energy metabolism

Kun Zhang, Qiuhua Liang. Research progress on the mechanism and treatment of mitochondrial dysfunction in arterial medial calcification[J]. Chinese Journal of Diagnostics(Electronic Edition), 2025, 13(03): 171-176.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhzdxdzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-655X.2025.03.005

https://zhzdxdzzz.cma-cmc.com.cn/EN/Y2025/V13/I03/171

Figures/Tables 2

References 56

[1]	Lee SJ，Lee IK，Jeon JH.Vascular calcification-new insights into its mechanism[J]．Int J Mol Sci，2020，21(8)：2685.DOI：10.3390/ijms21082685.
[2]	Lanzer P，Hannan FM，Lanzer JD，et al.Medial arterial calcification：JACC state-of-the-art review[J]．J Am Coll Cardiol，2021，78(11)：1145-1165.DOI：10.1016/j.jacc.2021.06.049.
[3]	Li M，Zhu Y，Jaiswal SK，et al.Mitochondria homeostasis and vascular medial calcification[J]．Calcif Tissue Int，2021，109(2)：113-120.DOI：10.1007/s00223-021-00828-1.
[4]	Tang HY，Chen AQ，Zhang H，et al.Vascular smooth muscle cells phenotypic switching in cardiovascular diseases[J]．Cells，2022，11(24)：4060.DOI：10.3390/cells11244060.
[5]	Annesley SJ，Fisher PR.Mitochondria in health and disease [J]．Cells，2019，8(7)：680.DOI：10.3390/cells8070680.
[6]	Li AL，Lian L，Chen XN，et al.The role of mitochondria in myocardial damage caused by energy metabolism disorders：from mechanisms to therapeutics[J]．Free Radic Biol Med，2023(208)：236-251.DOI：10.1016/j.freeradbiomed.2023.08.009.
[7]	Jiang M, Wang L, Sheng H. Mitochondria in depression：the dysfunction of mitochondrial energy metabolism and quality control systems[J]．CNS Neurosci Ther，2024，30(2)：e14576.DOI：10.1111/cns.14576.
[8]	Yang S，Lian G．ROS and diseases：role in metabolism and energy supply[J]．Mol Cell Biochem，2020，467(1-2)：1-12.DOI：10.1007/s11010-019-03667-9.
[9]	Bertero E，Maack C．Calcium signaling and reactive oxygen species in mitochondria[J]．Circ Res，2018，122(10)：1460-1478.DOI：10.1161/CIRCRESAHA.118.310082.
[10]	Mittler R．ROS are good [J]．Trends Plant Sci，2017，22(1)：11-19.DOI：10.1016/j.tplants.2016.08.002.
[11]	Chan DC.Mitochondrial dynamics and its involvement in disease[J]．Annu Rev Pathol，2020(15)：235-259.DOI：10.1146/annurev-pathmechdis-012419-032711.
[12]	Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease：mechanisms and potential targets[J]．Signal Transduct Target Ther，2023，8(1)：333.DOI：10.1038/s41392-023-01547-9.
[13]	Quintana-Cabrera R, Scorrano L. Determinants and outcomes of mitochondrial dynamics [J]．Mol Cell，2023，83(6)：857-876.DOI：10.1016/j.molcel.2023.02.012.
[14]	Lu Y，Li Z，Zhang S，et al.Cellular mitophagy：mechanism，roles in diseases and small molecule pharmacological regulation[J]．Theranostics，2023，13(2)：736-766.DOI：10.7150/thno.79876.
[15]	Onishi M，Yamano K，Sato M，et al.Molecular mechanisms and physiological functions of mitophagy [J]．Embo J，2021，40(3)：e104705.DOI：10.15252/embj.2020104705.
[16]	Byon CH，Javed A，Dai Q，et al.Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling[J]．J Biol Chem，2008，283(22)：15319-15327.DOI：10.1074/jbc.M800021200.
[17]	Shi J，Yang Y，Cheng A，et al.Metabolism of vascular smooth muscle cells in vascular diseases [J]．Am J Physiol Heart Circ Physiol，2020，319(3)：H613-H631.DOI：10.1152/ajpheart.00220.2020.
[18]	Zeng ZL，Yuan Q，Zu X，et al.Insights into the role of mitochondria in vascular calcification[J]．Front Cardiovasc Med，2022(9)：879752.DOI：10.3389/fcvm.2022.879752.
[19]	He L，Zhou Q，Huang Z，et al.PINK1/Parkin-mediated mitophagy promotes apelin-13-induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions[J]．J Cell Physiol，2019，234(6)：8668-8682.DOI：10.1002/jcp.27527.
[20]	Voelkl J，Egli-Spichtig D，Alesutan I，et al.Inflammation：a putative link between phosphate metabolism and cardiovascular disease[J]．Clin Sci (Lond)，2021，135(1)：201-227.DOI：10.1042/CS20190895.
[21]	Raikou VD，Kyriaki D，Gavriil S．Importance of serum phosphate in elderly patients with diabetes mellitus[J]．World J Diabetes，2020，11(10)：416-424.DOI：10.4239/wjd.v11.i10.416.
[22]	Crouthamel MH，Lau WL，Leaf EM，et al.Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells：redundant roles for PiT-1 and PiT-2[J]．Arterioscler Thromb Vasc Biol，2013，33(11)：2625-2632.DOI：10.1161/ATVBAHA.113.302249.
[23]	Nguyen NT，Nguyen TT，Da Ly D, et al. Oxidative stress by Ca^2＋ overload is critical for phosphate-induced vascular calcification[J]．Am J Physiol Heart Circ Physiol，2020，319(6)：H1302-H1312.DOI：10.1152/ajpheart.00305.2020.
[24]	Rashdan NA，Sim AM，Cui L，et al.Osteocalcin regulates arterial calcification via altered Wnt signaling and glucose metabolism[J]．J Bone Miner Res，2020，35(2)：357-367.DOI：10.1002/jbmr.3888.
[25]	Lee SJ，Jeong JY，Oh CJ，et al.Pyruvate dehydrogenase kinase 4 promotes vascular calcification via SMAD1/5/8 phosphorylation[J]．Sci Rep，2015(5)：16577.DOI：10.1038/srep16577.
[26]	Saelens X, Festjens N, Vande Walle L, et al. Toxic proteins released from mitochondria in cell death[J]．Oncogene，2004，23(16)：2861-2874.DOI：10.1038/sj.onc.1207523.
[27]	Hill MM，Adrain C，Duriez PJ，et al.Analysis of the composition，assembly kinetics and activity of native Apaf-1 apoptosomes[J]．EMBO J，2004，23(10)：2134-2145.DOI：10.1038/sj.emboj.7600210.
[28]	Kim H，Kim HJ，Lee K，et al.α-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway[J]．J Cell Mol Med，2012，16(2)：273-286.DOI：10.1111/j.1582-4934.2011.01294.x.
[29]	Cui L，Li Z，Chang X，et al.Quercetin attenuates vascular calcification by inhibiting oxidative stress and mitochondrial fission[J]．Vascul Pharmacol，2017(88)：21-29.DOI：10.1016/j.vph.2016.11.006.
[30]	Huang M, Zheng L, Xu H, et al. Oxidative stress contributes to vascular calcification in patients with chronic kidney disease[J]．J Mol Cell Cardiol，2020(138)：256-268.DOI：10.1016/j.yjmcc.2019.12.006.
[31]	Chen NX，Duan D，O′Neill KD，et al.High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells[J]．Nephrol Dial Transplant，2006，21(12)：3435-3442.DOI：10.1093/ndt/gfl429.
[32]	Weinberg Sibony R，Segev O，Dor S，et al.Overview of oxidative stress and inflammation in diabetes[J]．J Diabetes，2024，16(10)：e70014.DOI：10.1111/1753-0407.70014.
[33]	Basta G，Lazzerini G，Del Turco S，et al.At least 2 distinct pathways generating reactive oxygen species mediate vascular cell adhesion molecule-1 induction by advanced glycation end products[J]．Arterioscler Thromb Vasc Biol，2005，25(7)：1401-1407.DOI：10.1161/01.ATV.0000167522.48370.5e.
[34]	Liu Y, Li J, Han Y, et al. Advanced glycation end-products suppress autophagy by AMPK/mTOR signaling pathway to promote vascular calcification[J]．Mol Cell Biochem，2020，471(1-2)：91-100.DOI：10.1007/s11010-020-03769-9.
[35]	Ma WQ, Han XQ, Wang Y, et al. Nε-carboxymethyl-lysine promotes calcium deposition in VSMCs via intracellular oxidative stress-induced PDK4 activation and alters glucose metabolism[J]．Oncotarget，2017，8(68)：112841-112854.DOI：10.18632/oncotarget.22835.
[36]	Zhu Y，Ma WQ，Han XQ，et al.Advanced glycation end products accelerate calcification in VSMCs through HIF-1α/PDK4 activation and suppress glucose metabolism[J]．Sci Rep，2018，8(1)：13730.DOI：10.1038/s41598-018-31877-6.
[37]	Kay AM, Simpson CL, Stewart JA Jr. The role of AGE/RAGE signaling in diabetes-mediated vascular calcification[J]．J Diabetes Res，2016(2016)：6809703.DOI：10.1155/2016/6809703.
[38]	Ishitobi M, Hosaka T, Morita N, et al. Serum lactate levels are associated with serum alanine aminotransferase and total bilirubin levels in patients with type 2 diabetes mellitus：a cross-sectional study[J]．Diabetes Res Clin Pract，2019(149)：1-8.DOI：10.1016/j.diabres.2019.01.028.
[39]	Broskey NT，Zou K，Dohm GL，et al.Plasma lactate as a marker for metabolic health[J]．Exerc Sport Sci Rev，2020，48(3)：119-124.DOI：10.1249/JES.0000000000000220.
[40]	Zhu Y，Han XQ，Sun XJ，et al.Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy[J]．Apoptosis，2020，25(5/6)：321-340.DOI：10.1007/s10495-020-01592-7.
[41]	Zhu Y，Zhang JL，Yan XJ，et al. Exploring a new mechanism between lactate and VSMC calcification：PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis[J]．Cell Death Dis，2023，14(9)：598.DOI：10.1038/s41419-023-06113-3.
[42]	Kozlov AM, Lone A, Betts DH, et al. Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts[J]．Sci Rep，2020，10(1)：8388.DOI：10.1038/s41598-020-65193-9.
[43]	Tang FT，Chen SR，Wu XQ，et al.Hypercholesterolemia accelerates vascular calcification induced by excessive vitamin D via oxidative stress[J]．Calcif Tissue Int，2006，79(5)：326-339.DOI：10.1007/s00223-006-0004-8.
[44]	Swiader A，Nahapetyan H，Faccini J，et al.Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids[J]．Oncotarget，2016，7(20)：28821-28835.DOI：10.18632/oncotarget.8936.
[45]	Dwyer JR，Sever N，Carlson M，et al.Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells[J]．J Biol Chem，2007，282(12)：8959-8968.DOI：10.1074/jbc.M611741200.
[46]	Brodeur MR，Bouvet C，Barrette M，et al.Palmitic acid increases medial calcification by inducing oxidative stress[J]．J Vasc Res，2013，50(5)：430-441.DOI：10.1159/000354235.
[47]	Shao JS，Cheng SL，Pingsterhaus JM，et al.Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals[J]．J Clin Invest，2005，115(5)：1210-1220.DOI：10.1172/JCI24140.
[48]	Sun K，Tang X，Song S，et al.Hyperoxalemia leads to oxidative stress in endothelial cells and mice with chronic kidney disease[J]．Kidney Blood Press Res，2021，46(3)：377-386.DOI：10.1159/000516013.
[49]	Henze LA，Luong T，Boehme B，et al.Impact of C-reactive protein on osteo-/chondrogenic transdifferentiation and calcification of vascular smooth muscle cells[J]．Aging (Albany NY)，2019，11(15)：5445-5462.DOI：10.18632/aging.102130.
[50]	Raghuraman G，Hsiung J，Zuniga MC，et al.Eotaxin augments calcification in vascular smooth muscle cells[J]．J Cell Biochem，2017，118(3)：647-654.DOI：10.1002/jcb.25752.
[51]	Petsophonsakul P, Burgmaier M, Willems B, et al. Nicotine promotes vascular calcification via intracellular Ca2＋-mediated，Nox5-induced oxidative stress，and extracellular vesicle release in vascular smooth muscle cells[J]．Cardiovasc Res，2022，118(9)：2196-2210.DOI：10.1093/cvr/cvab244.
[52]	Chen WR，Zhou YJ，Sha Y，et al.Melatonin attenuates vascular calcification by inhibiting mitochondria fission via an AMPK/Drp1 signalling pathway[J]．J Cell Mol Med，2020，24(11)：6043-6054.DOI：10.1111/jcmm.15157.
[53]	Ma WQ，Sun XJ，Wang Y，et al.Restoring mitochondrial biogenesis with metformin attenuates β-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of PDK4/oxidative stress-mediated apoptosis[J]．Mol Cell Endocrinol，2019(479)：39-53.DOI：10.1016/j.mce.2018.08.012.
[54]	Zhang P，Li Y，Du Y，et al.Resveratrol ameliorated vascular calcification by regulating Sirt-1 and Nrf2[J]．Transplant Proc，2016，48(10)：3378-3386.DOI：10.1016/j.transproceed.2016.10.023.
[55]	Cui L，Zhou Q，Zheng X，et al.Mitoquinone attenuates vascular calcification by suppressing oxidative stress and reducing apoptosis of vascular smooth muscle cells via the Keap1/Nrf2 pathway[J]．Free Radic Biol Med，2020(161)：23-31.DOI：10.1016/j.freeradbiomed.2020.09.028.
[56]	Wang PW，Pang Q，Zhou T，et al.Irisin alleviates vascular calcification by inhibiting VSMC osteoblastic transformation and mitochondria dysfunction via AMPK/Drp1 signaling pathway in chronic kidney disease[J]．Atherosclerosis，2022(346)：36-45.DOI：10.1016/j.atherosclerosis.2022.02.007.

治疗措施	信号分子	线粒体改变	血管平滑肌细胞改变	参考文献
褪黑素	AMPK/Drp1	线粒体裂变、超氧化物、mPTP(－) ATP合成、MMP (＋)	Runx2、ALP(－)	[52]
槲皮素	Drp1	线粒体裂变、ROS水平、细胞色素c释放(－) ATP合成、MMP(＋)	减少钙沉积	[29]
二甲双胍	AMPK/PDK4	细胞凋亡、ROS水平(－) 线粒体自噬、ATP合成、MMP、线粒体生物合成(＋)	Runx2、BMP2、ALP(－) SM-22α(＋)	[53]
α-硫辛酸	Gas6/Axl/Akt	细胞凋亡、超氧化物(－) ATP合成(＋)，改善线粒体嵴结构	减少钙沉积	[28]
白藜芦醇	Sirt1，Nrf2，FGF-23	ROS水平、细胞凋亡、Ca^2＋(－)	减少钙沉积，Runx2、OPN(－)	[54]
米托醌	Nrf2/Keap1	ROS水平、细胞凋亡(－) SOD(＋)	减少钙沉积	[55]
鸢尾素	AMPK，Drp1，Mfn2	线粒体裂变、细胞凋亡、ROS水平(－) SOD、ATP合成、线粒体融合(＋)	Runx2、BMP2(－) α-SMA、SM-22α(＋)	[56]

治疗措施	信号分子	线粒体改变	血管平滑肌细胞改变	参考文献
褪黑素	AMPK/Drp1	线粒体裂变、超氧化物、mPTP(－) ATP合成、MMP (＋)	Runx2、ALP(－)	[52]
槲皮素	Drp1	线粒体裂变、ROS水平、细胞色素c释放(－) ATP合成、MMP(＋)	减少钙沉积	[29]
二甲双胍	AMPK/PDK4	细胞凋亡、ROS水平(－) 线粒体自噬、ATP合成、MMP、线粒体生物合成(＋)	Runx2、BMP2、ALP(－) SM-22α(＋)	[53]
α-硫辛酸	Gas6/Axl/Akt	细胞凋亡、超氧化物(－) ATP合成(＋)，改善线粒体嵴结构	减少钙沉积	[28]
白藜芦醇	Sirt1，Nrf2，FGF-23	ROS水平、细胞凋亡、Ca^2＋(－)	减少钙沉积，Runx2、OPN(－)	[54]
米托醌	Nrf2/Keap1	ROS水平、细胞凋亡(－) SOD(＋)	减少钙沉积	[55]
鸢尾素	AMPK，Drp1，Mfn2	线粒体裂变、细胞凋亡、ROS水平(－) SOD、ATP合成、线粒体融合(＋)	Runx2、BMP2(－) α-SMA、SM-22α(＋)	[56]

Please choose a citation manager

Content to export