当前位置: X-MOL 学术J. Inherit. Metab. Dis. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Increased protein propionylation contributes to mitochondrial dysfunction in liver cells and fibroblasts, but not in myotubes
Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2020-08-02 , DOI: 10.1002/jimd.12296
Bart Lagerwaard 1, 2 , Olga Pougovkina 3 , Anna F Bekebrede 1 , Heleen Te Brinke 3 , Ronald J A Wanders 3, 4 , Arie G Nieuwenhuizen 1 , Jaap Keijer 1 , Vincent C J de Boer 1, 3, 4
Affiliation  

Post‐translational protein modifications derived from metabolic intermediates, such as acyl‐CoAs, have been shown to regulate mitochondrial function. Patients with a genetic defect in the propionyl‐CoA carboxylase (PCC) gene clinically present symptoms related to mitochondrial disorders and are characterised by decreased mitochondrial respiration. Since propionyl‐CoA accumulates in PCC deficient patients and protein propionylation can be driven by the level of propionyl‐CoA, we hypothesised that protein propionylation could play a role in the pathology of the disease. Indeed, we identified increased protein propionylation due to pathologic propionyl‐CoA accumulation in patient‐derived fibroblasts and this was accompanied by defective mitochondrial respiration, as was shown by a decrease in complex I‐driven respiration. To mimic pathological protein propionylation levels, we exposed cultured fibroblasts, Fao liver cells and C2C12 muscle myotubes to propionate levels that are typically found in these patients. This induced a global increase in protein propionylation and histone protein propionylation and was also accompanied by a decrease in mitochondrial respiration in liver and fibroblasts. However, in C2C12 myotubes propionate exposure did not decrease mitochondrial respiration, possibly due to differences in propionyl‐CoA metabolism as compared to the liver. Therefore, protein propionylation could contribute to the pathology in these patients, especially in the liver, and could therefore be an interesting target to pursue in the treatment of this metabolic disease.

中文翻译:

增加的蛋白质丙酰化会导致肝细胞和成纤维细胞的线粒体功能障碍,但不会导致肌管

来自代谢中间体(如酰基辅酶A)的翻译后蛋白质修饰已被证明可以调节线粒体功能。丙酰辅酶 A 羧化酶 (PCC) 基因遗传缺陷的患者临床表现出与线粒体疾病相关的症状,其特征是线粒体呼吸减弱。由于丙酰辅酶A在PCC缺陷患者中积累并且蛋白质丙酰化可以由丙酰辅酶A的水平驱动,我们假设蛋白质丙酰化可能在该疾病的病理学中起作用。事实上,我们发现由于患者来源的成纤维细胞中病理性丙酰辅酶 A 积累导致蛋白质丙酰化增加,这伴随着线粒体呼吸缺陷,如复合 I 驱动呼吸的减少所示。为了模拟病理性蛋白质丙酰化水平,我们将培养的成纤维细胞、Fao 肝细胞和 C2C12 肌肉肌管暴露于这些患者中通常存在的丙酸水平。这诱导了蛋白质丙酰化和组蛋白丙酰化的整体增加,并且还伴随着肝脏和成纤维细胞中线粒体呼吸的减少。然而,在 C2C12 肌管中,丙酸暴露并未减少线粒体呼吸,这可能是由于与肝脏相比丙酰辅酶 A 代谢存在差异。因此,蛋白质丙酰化可能导致这些患者的病理,尤其是肝脏,因此可能是治疗这种代谢疾病的一个有趣的目标。Fao 肝细胞和 C2C12 肌肉肌管达到通常在这些患者中发现的丙酸水平。这诱导了蛋白质丙酰化和组蛋白丙酰化的整体增加,并且还伴随着肝脏和成纤维细胞中线粒体呼吸的减少。然而,在 C2C12 肌管中,丙酸暴露并未减少线粒体呼吸,这可能是由于与肝脏相比丙酰辅酶 A 代谢存在差异。因此,蛋白质丙酰化可能导致这些患者的病理,尤其是肝脏,因此可能是治疗这种代谢疾病的一个有趣的目标。Fao 肝细胞和 C2C12 肌肉肌管达到通常在这些患者中发现的丙酸水平。这诱导了蛋白质丙酰化和组蛋白丙酰化的整体增加,并且还伴随着肝脏和成纤维细胞中线粒体呼吸的减少。然而,在 C2C12 肌管中,丙酸暴露并未减少线粒体呼吸,这可能是由于与肝脏相比丙酰辅酶 A 代谢存在差异。因此,蛋白质丙酰化可能导致这些患者的病理,尤其是肝脏,因此可能是治疗这种代谢疾病的一个有趣的目标。这诱导了蛋白质丙酰化和组蛋白丙酰化的整体增加,并且还伴随着肝脏和成纤维细胞中线粒体呼吸的减少。然而,在 C2C12 肌管中,丙酸暴露并未减少线粒体呼吸,这可能是由于与肝脏相比丙酰辅酶 A 代谢存在差异。因此,蛋白质丙酰化可能导致这些患者的病理,尤其是肝脏,因此可能是治疗这种代谢疾病的一个有趣的目标。这诱导了蛋白质丙酰化和组蛋白丙酰化的整体增加,并且还伴随着肝脏和成纤维细胞中线粒体呼吸的减少。然而,在 C2C12 肌管中,丙酸暴露并未减少线粒体呼吸,这可能是由于与肝脏相比丙酰辅酶 A 代谢存在差异。因此,蛋白质丙酰化可能导致这些患者的病理,尤其是肝脏,因此可能是治疗这种代谢疾病的一个有趣的目标。
更新日期:2020-08-02
down
wechat
bug