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

Cell Death & Disease
Wen-Qi MaNai-Feng Liu

Abstract

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 autopha...Continue Reading

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Methods Mentioned

BETA
nuclear translocation
transfection
confocal microscopy
transmission electron microscopy
flow cytometry
Protein Assay
electrophoresis
PCR

Software Mentioned

SPSS
Seahorse XF Analyser
GraphPad Prism
Image J

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Apoptosis

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