Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Due to inefficient propionate catabolism patients are endangered by life-threatening ketoacidotic crisis. Protein and amino acid restriction are major therapeutic pillars. However, long-term complications like neurological deterioration and cardiac abnormalities cannot be prevented. Chronic kidney disease (CKD), which is a well-known characteristic of methylmalonic aciduria two enzymatic steps downstream from PCC, has been recognized as a novel late-onset complication in PA. The pathophysiology of CKD in PA is unclear. We investigated mitochondrial structure and metabolism in human renal tubular cells of healthy controls and PA patients. The cells were exposed to either standard cell culture conditions (NT), high protein (HP) or high concentrations of isoleucine and valine (I/V). Mitochondrial morphology changed to condensed, fractured morphology in PA cells irrespective of the cell culture medium. HP and I/V exposure, however, potentiated oxidative stress in PA cells. Mitochondrial mass was enriched in PA cells, and further increased by HP and I/V exposure suggesting a need for compensation. Alterations in the tricarboxylic acid cycle intermediates and accumulation of medium- and long-chain acylcarnitines pointed to altered mitochondrial energy metabolism. Mitophagy was silenced while autophagy as cellular defense mechanisms was highly active in PA cells. The data demonstrate that PA is associated with renal mitochondrial damage which is aggravated by protein and I/V load. Preservation of mitochondrial energy homeostasis in renal cells may be a potential future therapeutic target.

中文翻译：

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丙酸尿症中的蛋白质暴露增强了肾上皮细胞中的线粒体损伤

丙酸尿症 (PA) 是由线粒体酶丙酰辅酶 A 羧化酶 (PCC) 缺乏引起的。由于低效的丙酸盐分解代谢，患者面临危及生命的酮症酸中毒危机。蛋白质和氨基酸限制是主要的治疗支柱。然而，无法预防神经功能恶化和心脏异常等长期并发症。慢性肾脏病 (CKD) 是 PCC 下游两个酶促步骤的甲基丙二酸尿症的一个众所周知的特征，已被认为是 PA 中一种新型的迟发性并发症。PA中CKD的病理生理学尚不清楚。我们研究了健康对照和 PA 患者的人肾小管细胞中的线粒体结构和代谢。将细胞暴露于标准细胞培养条件 (NT)、高蛋白 (HP) 或高浓度的异亮氨酸和缬氨酸 (I/V)。无论细胞培养基如何，PA 细胞中的线粒体形态都变为浓缩、断裂的形态。然而，HP 和 I/V 暴露会增强 PA 细胞中的氧化应激。线粒体质量在 PA 细胞中富集，并且通过 HP 和 I/V 暴露进一步增加，表明需要补偿。三羧酸循环中间体的变化和中长链酰基肉碱的积累表明线粒体能量代谢的改变。线粒体自噬被沉默，而自噬作为细胞防御机制在 PA 细胞中高度活跃。数据表明，PA 与肾线粒体损伤有关，而肾线粒体损伤会因蛋白质和 I/V 负荷而加重。