Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
Jining Key Laboratory of Pharmacology, Jining Medical University, Shandong 272067, China.; School of Basic Medicine, Jining Medical University, Shandong 272067, China.
Pharmacol Ther. 2023 Sep;249:108501. doi: 10.1016/j.pharmthera.2023.108501. Epub 2023 Jul 22.
Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), which is responsible for converting propionyl-CoA to methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle. When this process is disrupted, propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening cardiac diseases and other metabolic strokes. While the clinical symptoms and diagnosis of PA are well established, the underlying pathophysiological mechanisms of PA-induced diseases are not fully understood. As a result, there are currently few effective therapies for PA beyond dietary restriction. This review focuses on the pathophysiological mechanisms of the various complications associated with PA, drawing on extensive research and clinical reports. Most research suggests that propionyl-CoA and its metabolites can impair mitochondrial energy metabolism and cause cellular damage by inducing oxidative stress. However, direct evidence from in vivo studies is still lacking. Additionally, elevated levels of ammonia can be toxic, although not all PA patients develop hyperammonemia. The discovery of pathophysiological mechanisms underlying various complications associated with PA can aid in the development of more effective therapeutic treatments. The consequences of elevated odd-chain fatty acids in lipid metabolism and potential gene expression changes mediated by histone propionylation also warrant further investigation.
丙酸血症（PA）是一种遗传性代谢紊乱疾病，由线粒体酶丙酰基辅酶 A 羧化酶（PCC）的基因突变引起，该酶负责将丙酰基辅酶 A 转化为甲基丙二酰基辅酶 A，以便进一步在三羧酸循环中代谢。当这个过程被打乱时，丙酰基辅酶 A 及其代谢物会积累，导致各种并发症，包括危及生命的心脏病和其他代谢性中风。虽然 PA 的临床症状和诊断已经得到很好的确立，但 PA 引起的疾病的潜在病理生理机制还不完全清楚。因此，除了饮食限制外，目前针对 PA 几乎没有有效的治疗方法。本综述重点关注与 PA 相关的各种并发症的病理生理机制，参考了广泛的研究和临床报告。大多数研究表明，丙酰基辅酶 A 及其代谢物可以通过诱导氧化应激来损害线粒体能量代谢并导致细胞损伤。然而，目前仍缺乏来自体内研究的直接证据。此外，氨水平升高可能有毒性，尽管并非所有 PA 患者都会出现高氨血症。发现与 PA 相关的各种并发症的病理生理机制有助于开发更有效的治疗方法。脂质代谢中奇数链脂肪酸升高的后果以及组蛋白丙酰化介导的潜在基因表达变化也值得进一步研究。
