Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, P.R. China.
Cell Death Dis. 2020 Nov 17;11(11):991. doi: 10.1038/s41419-020-03162-w.
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.
丙酮酸脱氢酶激酶 4（PDK4）是细胞能量调节中重要的线粒体基质酶。先前的研究表明，PDK4 在动脉粥样硬化患者的钙化血管中增加，并且与线粒体功能密切相关，但确切的调节机制在很大程度上仍然未知。本研究旨在探讨 PDK4 在血管钙化中的作用及其涉及的分子机制。使用各种互补技术，我们发现血管平滑肌细胞（VSMCs）钙化过程中自噬活性受损，而敲低 PDK4 则产生相反的效果。PDK4 促使 VSMCs 的代谢重编程向瓦博格效应转变，而 PDK4 的抑制则消除了 VSMCs 的钙化。在机制上，PDK4 破坏了线粒体相关内质网膜的完整性，同时损害了线粒体呼吸能力，这通过抑制 V-ATP 酶和乳酸脱氢酶 B 的相互作用导致溶酶体降解减少。PDK4 还抑制转录因子 EB 的核易位，从而抑制溶酶体功能。这些变化导致自噬流中断，从而加速 VSMCs 中的钙沉积。此外，糖酵解作为一种代谢适应，可提高 VSMCs 的氧化应激抗性，而 2-脱氧-D-葡萄糖抑制糖酵解会诱导 VSMCs 凋亡并增加 VSMCs 中的钙沉积。我们的结果表明，PDK4 通过自噬抑制和代谢重编程在血管钙化中发挥关键作用。
