Lactate accelerates calcification in VSMCs through suppression of BNIP3-mediated mitophagy

Zhu, Yi; Ji, Jingjing; Yang, Rui; Han, Xi‐Qiong; Sun, Xuejiao; Ma, Wen-Qi; Liu, Naifeng

doi:10.1016/j.cellsig.2019.03.006

Cited by 55 publications

(42 citation statements)

References 57 publications

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“…In turn, induced apoptosis generates oxidative stress, further mitochondrial dysfunction, apoptotic bodies, and MVs [135][136][137][138], events that have been mechanistically linked to DNA damage, ER stress, autophagy or mitophagy, and calcium phosphate deposition. It can also induce osteogenic gene induction and transformation into osteogenic phenotype of VSMCs [139][140][141][142]. Apoptosis is not mutually exclusive, but actually complementary to other pathways introduced in this review that eventually lead to VC.…”

Section: Apoptosismentioning

confidence: 81%

“…In that work, exogenous lactate treatment accelerated VSMC calcification, along with impaired mitochondrial function, as evidenced by the opening rate of the mitochondrial permeability transition pore, depolarization of mitochondrial membrane potential, and downregulation of mitochondrial biogenesis markers. Intriguingly, lactate inhibited mitophagy, whereas BCL2-Interacting Protein 3 (BNIP3)-mediated mitophagy restored mitochondrial function, biogenesis, and reversed lactate-induced VSMC calcification [139] (Figure 3). The same authors identified a nuclear receptor, NR4A1, as an inhibitor of mitophagy, as well as a promoter of mitochondrial fission [295].…”

Section: Mitochondrial Dysfunction and Defective Mitophagy In Vascumentioning

confidence: 99%

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Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

233

219

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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

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Section: Apoptosismentioning

confidence: 81%

Section: Mitochondrial Dysfunction and Defective Mitophagy In Vascumentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

233

219

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“…The proper function of mitochondria and ER is of importance to cellular homeostasis, whereas dysfunction at either site or perturbation of ER-mitochondria contact has also been reported in various models of metabolicrelated diseases, including insulin resistance 39 , diabetic cardiomyopathy 40 and obesity 24 . Mitochondrial dysfunction contributes to accelerated cell apoptosis, inflammation, excessive ROS production, lactate accumulation, and a deficient ATP supply due to the reduced oxidative phosphorylation of glucose, and all of these factors could promote vascular calcification 41,42 . Similarly, ER stressmediated apoptosis is also involved in vascular calcification 43 .…”

Section: Discussionmentioning

confidence: 99%

PDK4 promotes vascular calcification by interfering with autophagic activity and metabolic reprogramming

Sun

Zhu

et al. 2020

Cell Death Dis

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Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy regulation. Previous studies suggested that PDK4 is increased in the calcified vessels of patients with atherosclerosis and is closely associated with mitochondrial function, but the precise regulatory mechanisms remain largely unknown. This study aims to investigate the role of PDK4 in vascular calcification and the molecular mechanisms involved. Using a variety of complementary techniques, we found impaired autophagic activity in the process of vascular smooth muscle cells (VSMCs) calcification, whereas knocking down PDK4 had the opposite effect. PDK4 drives the metabolic reprogramming of VSMCs towards a Warburg effect, and the inhibition of PDK4 abrogates VSMCs calcification. Mechanistically, PDK4 disturbs the integrity of the mitochondria-associated endoplasmic reticulum membrane, concomitantly impairing mitochondrial respiratory capacity, which contributes to a decrease in lysosomal degradation by inhibiting the V-ATPase and lactate dehydrogenase B interaction. PDK4 also inhibits the nuclear translocation of the transcription factor EB, thus inhibiting lysosomal function. These changes result in the interruption of autophagic flux, which accelerates calcium deposition in VSMCs. In addition, glycolysis serves as a metabolic adaptation to improve VSMCs oxidative stress resistance, whereas inhibition of glycolysis by 2-deoxy-D-glucose induces the apoptosis of VSMCs and increases the calcium deposition in VSMCs. Our results suggest that PDK4 plays a key role in vascular calcification through autophagy inhibition and metabolic reprogramming.

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“…Mitochondrial fusion and mitophagy play a pivotal role in the development of VC [6,7]. Optic atrophy 1 (OPA1) is a key regulator of mitochondrial fusion, and the AMP-activated protein kinase (AMPK)/OPA1 pathway is associated with mitochondrial fusion/mitophagy during cardiovascular disease [8,9].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway

Chen

Zhou

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Mitochondrial fusion/mitophagy plays a role in cardiovascular calcification. Melatonin has been shown to protect against cardiovascular disease. This study sought to explore whether melatonin attenuates vascular calcification by regulating mitochondrial fusion/mitophagy via the AMP-activated protein kinase/optic atrophy 1 (AMPK/OPA1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin Red S staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2), mitofusin 2 (Mfn2), mito-light chain 3 (mito-LC3) II, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated in response to melatonin, whereas Mfn2 and mito-LC3II were enhanced and accompanied by decreased mitochondrial superoxide levels. Melatonin also maintained mitochondrial function and promoted mitochondrial fusion/mitophagy via the OPA1 pathway. However, OPA1 deletion abolished the protective effects of melatonin on VSMC calcification. Melatonin treatment significantly increased p-AMPK and OPA1 protein expression, whereas treatment with compound C ablated the observed benefits of melatonin treatment. Collectively, our results demonstrate that melatonin protects VSMCs against calcification by promoting mitochondrial fusion/mitophagy via the AMPK/OPA1 pathway.

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Lactate accelerates calcification in VSMCs through suppression of BNIP3-mediated mitophagy

Cited by 55 publications

References 57 publications

Vascular Calcification—New Insights into Its Mechanism

Vascular Calcification—New Insights into Its Mechanism

PDK4 promotes vascular calcification by interfering with autophagic activity and metabolic reprogramming

Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway

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