Aging-Associated Metabolite Methylmalonic Acid Increases Susceptibility to Pulmonary Fibrosis

IF 4.7 2区 医学 Q1 PATHOLOGY American Journal of Pathology Pub Date : 2024-08-01 DOI:10.1016/j.ajpath.2024.04.011
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by pulmonary fibroblast overactivation, resulting in the accumulation of abnormal extracellular matrix and lung parenchymal damage. Although the pathogenesis of IPF remains unclear, aging was proposed as the most prominent nongenetic risk factor. Propionate metabolism undergoes reprogramming in the aging population, leading to the accumulation of the by-product methylmalonic acid (MMA). This study aimed to explore alterations in propionate metabolism in IPF and the impact of the by-product MMA on pulmonary fibrosis. It revealed alterations in the expression of enzymes involved in propionate metabolism within IPF lung tissues, characterized by an increase in propionyl-CoA carboxylase and methylmalonyl-CoA epimerase expression, and a decrease in methylmalonyl-CoA mutase expression. Knockdown of methylmalonyl-CoA mutase, the key enzyme in propionate metabolism, induced a profibrotic phenotype and activated co-cultured fibroblasts in A549 cells. MMA exacerbated bleomycin-induced mouse lung fibrosis and induced a profibrotic phenotype in both epithelial cells and fibroblasts through activation of the canonical transforming growth factor-β/Smad pathway. Overall, these findings unveil an alteration of propionate metabolism in IPF, leading to MMA accumulation, thus exacerbating lung fibrosis through promoting profibrotic phenotypic transitions via the canonical transforming growth factor-β/Smad signaling pathway.

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与衰老相关的代谢物甲基丙二酸增加肺纤维化的易感性
特发性肺纤维化(IPF)是一种进行性间质性肺病,其特点是肺成纤维细胞过度活化,导致异常细胞外基质(ECM)堆积和肺实质损伤。虽然 IPF 的发病机制仍不清楚,但衰老被认为是最主要的非遗传风险因素。以前的研究表明,老龄人群的丙酸代谢发生了重编程,导致副产品甲基丙二酸(MMA)的积累。本研究旨在探讨 IPF 中丙酸盐代谢的改变以及副产物甲基丙二酸对肺纤维化的影响。本研究揭示了 IPF 肺组织中参与丙酸盐代谢的酶表达的改变,其特点是丙酰-CoA 羧化酶(PCC)和甲基丙二酰-CoA 表聚酶(MCEE)的表达增加,而甲基丙二酰-CoA 突变酶(MUT)的表达减少。在 A549 细胞中敲除丙酸代谢的关键酶 MUT 会诱导促纤维化表型并激活共培养成纤维细胞。MMA 加剧了 BLM 诱导的小鼠肺纤维化,并通过激活典型 TGF-β/Smad 通路诱导上皮细胞和成纤维细胞形成促纤维化表型。总之,我们的研究结果揭示了 IPF 中丙酸盐代谢的改变,导致 MMA 积累,从而通过典型 TGF-β/Smad 信号通路促进促纤维化表型的转变,加重肺纤维化。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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