Pdk4, short for pyruvate dehydrogenase kinase 4, is a crucial mitochondrial matrix enzyme in cellular energy regulation. It inhibits the pyruvate dehydrogenase complex, thereby regulating the conversion of pyruvate to acetyl-CoA, which is a key step in the transition from glycolysis to the tricarboxylic acid cycle. This regulation impacts multiple metabolic pathways and is of great biological importance in processes such as metabolism, cell senescence, and disease development [1,2,3,4,5,6,7,8,9]. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, have been instrumental in understanding its functions.

In KO mouse models, Pdk4 -/- mice exhibit reduced mitochondria-associated endoplasmic reticulum membrane (MAM) formation and are protected against diet-induced skeletal muscle insulin resistance. This reveals that Pdk4 augments MAM formation during obesity, suppressing insulin signaling [2]. In vascular smooth muscle cells (VSMCs), knocking down Pdk4 improves autophagic activity and abrogates VSMCs calcification, suggesting Pdk4 promotes vascular calcification through autophagy inhibition and metabolic reprogramming [4]. Inhibition of Pdk4 in preclinical trials alleviates physical dysfunction and prevents age-associated frailty, as senescent cells' Pdk4-dependent hypercatabolism and lactate production promote cancer malignancy [1]. Also, in pancreatic ductal carcinoma cells, inhibiting Pdk4 enhances the anticancer activity of system xc-inhibitors in vitro and in suitable preclinical mouse models, as Pdk4 dictates metabolic resistance to ferroptosis [3].

In conclusion, Pdk4 is central in regulating metabolic processes and significantly impacts various disease conditions. Studies using KO/CKO mouse models have revealed its roles in cancer malignancy, insulin resistance, vascular calcification, and ferroptosis resistance. Understanding Pdk4's functions provides insights into potential therapeutic targets for age-related pathologies, diabetes-related complications, and cancer treatment.

References:

1. Dou, Xuefeng, Fu, Qiang, Long, Qilai, Zhao, Yuzheng, Sun, Yu. 2023. PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy. In Nature metabolism, 5, 1887-1910. doi:10.1038/s42255-023-00912-w. https://pubmed.ncbi.nlm.nih.gov/37903887/

2. Thoudam, Themis, Ha, Chae-Myeong, Leem, Jaechan, Rhee, Hyun-Woo, Lee, In-Kyu. 2018. PDK4 Augments ER-Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity. In Diabetes, 68, 571-586. doi:10.2337/db18-0363. https://pubmed.ncbi.nlm.nih.gov/30523025/

3. Song, Xinxin, Liu, Jiao, Kuang, Feimei, Xie, Yangchun, Tang, Daolin. . PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis. In Cell reports, 34, 108767. doi:10.1016/j.celrep.2021.108767. https://pubmed.ncbi.nlm.nih.gov/33626342/

4. Ma, Wen-Qi, Sun, Xue-Jiao, Zhu, Yi, Liu, Nai-Feng. 2020. PDK4 promotes vascular calcification by interfering with autophagic activity and metabolic reprogramming. In Cell death & disease, 11, 991. doi:10.1038/s41419-020-03162-w. https://pubmed.ncbi.nlm.nih.gov/33203874/

5. Li, Zihan, Peng, Yanxi, Li, Jiexin, Lin, Shuibin, Wang, Hongsheng. 2020. N6-methyladenosine regulates glycolysis of cancer cells through PDK4. In Nature communications, 11, 2578. doi:10.1038/s41467-020-16306-5. https://pubmed.ncbi.nlm.nih.gov/32444598/

6. Thoudam, Themis, Chanda, Dipanjan, Sinam, Ibotombi Singh, Jeon, Jae-Han, Lee, In-Kyu. 2022. Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2120157119. doi:10.1073/pnas.2120157119. https://pubmed.ncbi.nlm.nih.gov/35969774/

7. Ma, Zhouji, Ding, Youjun, Ding, Xiaofeng, Mo, Ran, Tan, Qian. 2023. PDK4 rescues high-glucose-induced senescent fibroblasts and promotes diabetic wound healing through enhancing glycolysis and regulating YAP and JNK pathway. In Cell death discovery, 9, 424. doi:10.1038/s41420-023-01725-2. https://pubmed.ncbi.nlm.nih.gov/38001078/

8. Gao, Yajing, Yan, Yan, Tripathi, Sushil, Katajisto, Pekka, Mäkelä, Tomi P. 2020. LKB1 Represses ATOH1 via PDK4 and Energy Metabolism and Regulates Intestinal Stem Cell Fate. In Gastroenterology, 158, 1389-1401.e10. doi:10.1053/j.gastro.2019.12.033. https://pubmed.ncbi.nlm.nih.gov/31930988/

9. Tian, Shasha, Yang, Xiaopeng, Lin, Yao, Yu, Pei, Zhao, Yanjun. 2024. PDK4-mediated Nrf2 inactivation contributes to oxidative stress and diabetic kidney injury. In Cellular signalling, 121, 111282. doi:10.1016/j.cellsig.2024.111282. https://pubmed.ncbi.nlm.nih.gov/38971568/