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

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 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.

PDK4-Mediated Metabolic Reprogramming Promotes Rituximab Resistance in Diffuse Large B-Cell Lymphoma Via Negative Regulation of MS4A1/CD20

“…Tumor cells undergo metabolic alteration to ful ll the bioenergetic and biosynthetic needs for rapid cell proliferation 45 . As an important mitochondrial matrix enzyme for cellular energy regulation 50 , PDK4 inhibits the entry of pyruvate into the TCA cycle, thus switching energy derivation to cytoplasmic glycolysis rather than mitochondrial OXPHOS 43,51 . Recently, DLBCL has been identi ed as a type of metabolic heterogeneity disease 9 .…”

“…Due to the absence of speci c modulator for PDK4, dichloroacetate (DCA), as a speci c inhibitor of PDK4 42,43 , was used to assess the impact of pharmacological PDK4 inhibition. Compared with rituximab alone, a signi cant increase of apoptosis was observed in cell lines when they were treated with rituximab (50 μg/mL) and DCA (5 mmol/L) for 48 hours (OCI-ly7: 20.25% ± 2.14% vs. 35.65% ± 3.87%, P = 0.0038; OCI-ly8: 13.63% ± 2.12% vs. 30.55% ± 3.39%, P = 0.0018), which is the case even in the U2932 cell line initially showing poor response to rituximab (5.54% ± 1.93% vs. 25.14% ± 3.66%, P = 0.0012; Fig.…”

Mitochondrial Dysfunction: Cause or Consequence of Vascular Calcification?

“…As discussed above, this metabolic shift is seen in both the calcified vessels of atherosclerotic patients (Lee et al, 2015 ) and calcified transdifferentiated VSMCs cultured under high Pi conditions (Rashdan et al, 2020 ). Recently, it has been demonstrated that PDK4 drives the metabolic reprogramming of VSMCs toward a high rate of glycolysis followed by lactic acid generation in the cytosol (Ma et al, 2020 ). Inhibition of PDK4 abrogates VSMCs calcification by inducing lysosomal function and autophagy (Ma et al, 2020 ).…”

“…Recently, it has been demonstrated that PDK4 drives the metabolic reprogramming of VSMCs toward a high rate of glycolysis followed by lactic acid generation in the cytosol (Ma et al, 2020 ). Inhibition of PDK4 abrogates VSMCs calcification by inducing lysosomal function and autophagy (Ma et al, 2020 ). In conclusion, enhancing autophagy in vascular calcification pathologies may have a multitude of additional effects including inhibiting the Warburg effect, suppressing saturated fatty acid–induced vascular calcification and aiding cellular survival by clearing away the damaged mitochondria via mitophagy.…”

κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling

“…Although this process is traditionally considered passive, degenerative, and quiescent, recent studies suggested that VC is an active process beginning with the deposition of cell-derived matrix vesicles into the extracellular matrix, where osteogenic differentiation plays a predominant role [ 4 – 6 ]. Ectopic osteogenesis driven by oxidative stress and metabolic are responsible for VC initiation [ 7 , 8 ].…”