Devabattula Geetanjali, Bakchi Bulti, Sharma Anamika, Sidhartha Nagamalli Naga, Dikundwar Amol G, Yeddanapudi Venkata Madhavi, Godugu Chandraiah
Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India.
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India.
Biofactors. 2025 Jul-Aug;51(4):e70032. doi: 10.1002/biof.70032.
Pulmonary fibrosis is a debilitating condition characterized by excessive collagen deposition and scar formation. Divergent factors often contribute to mitochondrial dysfunction. Oxidative stress is one of the major triggers for the development of pulmonary fibrosis through downregulation of SIRT3. This study aims to enhance the SIRT3 activity at the organelle level by a targeted drug delivery approach. C12 is a known molecule as a SIRT3 activator and is protective in pulmonary fibrosis in our previous studies. We have designed a mitochondrial-targeted delivery approach by introducing a triphenylphosphonium cation (TPP) into the C12 molecule to enhance its mitochondrial specificity and efficacy. The newly designed MitoC12 attenuated the BLM-induced acute lung injury and pulmonary fibrosis more effectively than C12 primarily through activation of SIRT3. The cellular uptake studies revealed that MitoC12 concentrated more in mitochondria than the cytosolic fraction. MitoC12 reduced BLM-induced oxidative stress in BEAS-2B cells and inhibited TGF-β-induced pulmonary fibrosis in MRC-5 cells. MitoC12 inhibited the EMT by decreasing the expression of vimentin and N-cadherin and increasing the expression of E-cadherin. Further, the in vivo studies of MitoC12 exhibited a protective effect in BLM-induced pulmonary fibrosis by improving lung function, decreasing inflammation, and restoring lung architecture. MitoC12 reduced the collagen deposition and expression of fibrotic markers such as TGF-β, collagen 1A and 3A, α-SMA, fibronectin, and vimentin. Mechanistically, MitoC12 showed an anti-fibrotic effect through activation of SIRT3 thereby preventing mitochondrial dyshomeostasis through regulating MnSOD and OGG1 functioning. Overall, this study suggests that MitoC12 could be a potential therapeutic option for pulmonary fibrosis emphasizing TPP-conjugated molecules in treating mitochondrial dysfunction-related diseases.
肺纤维化是一种以胶原蛋白过度沉积和瘢痕形成为特征的使人衰弱的病症。多种不同因素常导致线粒体功能障碍。氧化应激是通过下调SIRT3促进肺纤维化发展的主要触发因素之一。本研究旨在通过靶向药物递送方法在细胞器水平增强SIRT3活性。C12是一种已知的SIRT3激活剂分子，在我们先前的研究中对肺纤维化具有保护作用。我们通过将三苯基膦阳离子（TPP）引入C12分子设计了一种线粒体靶向递送方法，以增强其线粒体特异性和功效。新设计的MitoC12比C12更有效地减轻博来霉素诱导的急性肺损伤和肺纤维化，主要是通过激活SIRT3。细胞摄取研究表明，MitoC12在线粒体中的浓度高于胞质部分。MitoC12降低了博来霉素诱导的BEAS-2B细胞中的氧化应激，并抑制了转化生长因子-β诱导的MRC-5细胞中的肺纤维化。MitoC12通过降低波形蛋白和N-钙黏蛋白的表达并增加E-钙黏蛋白的表达来抑制上皮-间质转化。此外，MitoC12的体内研究通过改善肺功能、减轻炎症和恢复肺结构，对博来霉素诱导的肺纤维化表现出保护作用。MitoC12减少了胶原蛋白沉积以及纤维化标志物如转化生长因子-β、胶原蛋白1A和3A、α-平滑肌肌动蛋白、纤连蛋白和波形蛋白的表达。从机制上讲，MitoC12通过激活SIRT3显示出抗纤维化作用，从而通过调节锰超氧化物歧化酶和8-氧鸟嘌呤DNA糖基化酶1的功能来防止线粒体动态失衡。总体而言，本研究表明MitoC12可能是肺纤维化的一种潜在治疗选择，强调了TPP偶联分子在治疗线粒体功能障碍相关疾病中的作用。
