Piericidin A is a natural mitochondrial NADH-ubiquinone oxidoreductase (complex I) inhibitor [1]. Piericidin A is a potent neurotoxin and inhibits mitochondrial respiration by disrupting the electron transport system through its action on NADH-ubiquinone reductase[2]. Piericidin A has been widely used as a quorum-sensing inhibitor to suppress the expression of virulence genes in Erwinia carotovora subsp. atroseptica (Eca) [3].
In vitro, Piericidin A treatment for 48 hours significantly inhibited the viability of Tn5B1-4, HepG2, and Hek293 cells, with IC50 values of 0.061μM, 233.97μM, and 228.96μM, respectively[4]. Treatment of HT-29 cells with 100nM Piericidin A for 18 hours induced downregulation of GRP78 expression under low glucose conditions and was highly toxic to etoposide-resistant HT-29 cells[5]. Pretreatment with 100nM Piericidin A for 30min increased glucose uptake and consumption in C2C12 myoblasts without affecting Glut1 levels at the plasma membrane[6].
In vivo, Piericidin A treatment via a single intraperitoneal injection at a dose of 0.5mg/kg for 30min resulted in a significant reduction in partial pressure of arterial oxygen in mice[7]. Daily subcutaneous injection of Piericidin A at a dose of 0.5mg/kg for 28 days significantly increased pathologic phosphorylated tau levels in P301S+/+ mice and resulted in reduced cortical synaptic density[8].
References:
[1] Trost B M, Gholami H. Propene as an atom-economical linchpin for concise total synthesis of polyenes: piericidin A[J]. Journal of the American Chemical Society, 2018, 140(37): 11623-11626.
[2] Jeng M, Hall C, Crane F L, et al. Inhibition of mitochondrial electron transport by piericidin A and related compounds[J]. Biochemistry, 1968, 7(4): 1311-1322.
[3] Kang J E, Han J W, Jeon B J, et al. Efficacies of quorum sensing inhibitors, piericidin A and glucopiericidin A, produced by Streptomyces xanthocidicus KPP01532 for the control of potato soft rot caused by Erwinia carotovora subsp. atroseptica[J]. Microbiological research, 2016, 184: 32-41.
[4] Muhayimana S, Zhang X, Xu J, et al. Cytotoxic selectivity and apoptosis induction of piericidin A contributes potentially to its insecticidal effect against Mythimna separata (Lepidoptera: Noctuidae) larvae[J]. Pesticide Biochemistry and Physiology, 2019, 157: 19-25.
[5] Hwang J H, Kim J Y, Cha M R, et al. Etoposide‐resistant HT‐29 human colon carcinoma cells during glucose deprivation are sensitive to piericidin A, a GRP78 down‐regulator[J]. Journal of cellular physiology, 2008, 215(1): 243-250.
[6] Liemburg-Apers D C, Wagenaars J A L, Smeitink J A M, et al. Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR[J]. Journal of cell science, 2016, 129(23): 4411-4423.
[7] Schleifer G, Marutani E, Ferrari M, et al. Impaired hypoxic pulmonary vasoconstriction in a mouse model of Leigh syndrome[J]. American Journal of Physiology-Lung Cellular and Molecular Physiology, 2019, 316(2): L391-L399.
[8] Höllerhage M, Deck R, De Andrade A, et al. Piericidin A aggravates Tau pathology in P301S transgenic mice[J]. PLoS One, 2014, 9(12): e113557.
Piericidin A是一种天然的线粒体NADH-泛醌氧化还原酶（复合物I）抑制剂[1]。Piericidin A是一种强效神经毒素，通过作用于NADH-泛醌还原酶破坏电子传递系统，从而抑制线粒体呼吸[2]。Piericidin A已被广泛用作群体感应抑制剂，以抑制Erwinia carotovora subsp. atroseptica (Eca)中毒力基因的表达[3]。
在体外，Piericidin A处理48小时显著抑制了Tn5B1-4、HepG2和Hek293细胞的活力，IC50值分别为0.061µM、233.97µM和228.96µM[4]。使用100nM的Piericidin A处理HT-29细胞18小时，在低葡萄糖条件下诱导了GRP78表达的下调，并对依托泊苷耐药的HT-29细胞具有高毒性[5]。用100nM的Piericidin A预处理30分钟，增加了C2C12成肌细胞的葡萄糖摄取和消耗，而不影响质膜上的Glut1水平[6]。
在体内，单次腹腔注射0.5mg/kg剂量的Piericidin A 30分钟，导致小鼠动脉血氧分压显著降低[7]。每日皮下注射0.5mg/kg剂量的Piericidin A，持续28天，显著增加了P301S+/+小鼠的病理性磷酸化tau蛋白水平，并导致皮层突触密度降低[8]。