Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, 695011, India.
Dr B C Roy Multispeciality Medical Research Centre, Indian Institute of Technology, Kharagpur, Kharagpur, 721302, India.
Mol Cell Biochem. 2024 Feb;479(2):373-382. doi: 10.1007/s11010-023-04740-0. Epub 2023 Apr 19.
Chloroquine (CQ) has a long clinical history as an anti-malarial agent and also being used for the treatment of other infections and autoimmune diseases. Recently, this lysosomotropic agent and its derivatives are also been tested as adjuncts alongside conventional anti-cancer treatments in combinatorial therapies. However, their reported cardiotoxicity tends to raise concern over their indiscriminate use. Even though the influence of CQ and its derivatives on cardiac mitochondria is extensively studied in disease models, their impact on cardiac mitochondrial respiration under physiological conditions remains inconclusive. In this study, we aimed to evaluate the impact of CQ on cardiac mitochondrial respiration using both in-vitro and in-vivo model systems. Using high-resolution respirometry in isolated cardiac mitochondria from male C57BL/6 mice treated with intraperitoneal injection of 10 mg/kg/day of CQ for 14 days, CQ was found to impair substrate-mediated mitochondrial respiration in cardiac tissue. In an in-vitro model of H9C2 cardiomyoblasts, incubation with 50 µM of CQ for 24 h disrupted mitochondrial membrane potential, produced mitochondrial fragmentation, decreased mitochondrial respiration and induced superoxide generation. Altogether, our study results indicate that CQ has a deleterious impact on cardiac mitochondrial bioenergetics which in turn suggests that CQ treatment could be an added burden, especially in patients affected with diseases with underlying cardiac complications. As CQ is an inhibitor of the lysosomal pathway, the observed effect could be an outcome of the accumulation of dysfunctional mitochondria due to autophagy inhibition.
氯喹（CQ）作为一种抗疟药物已有很长的临床应用历史，也被用于治疗其他感染和自身免疫性疾病。最近，这种溶酶体靶向剂及其衍生物也被作为辅助药物与传统抗癌治疗联合应用于组合疗法中。然而，它们被报道的心脏毒性引起了人们对其滥用的关注。尽管 CQ 及其衍生物对疾病模型中心肌线粒体的影响已得到广泛研究，但它们对生理条件下心肌线粒体呼吸的影响仍不确定。在这项研究中，我们旨在使用体外和体内模型系统评估 CQ 对心脏线粒体呼吸的影响。通过对用腹腔注射 10mg/kg/天 CQ 处理 14 天的雄性 C57BL/6 小鼠的心脏线粒体进行高分辨率呼吸测定，发现 CQ 可损害心脏组织中底物介导的线粒体呼吸。在 H9C2 心肌细胞的体外模型中，孵育 24 小时 50µM 的 CQ 会破坏线粒体膜电位，导致线粒体碎片化，降低线粒体呼吸并诱导超氧化物生成。总的来说，我们的研究结果表明，CQ 对心脏线粒体生物能量学有有害影响，这反过来表明 CQ 治疗可能会增加负担，尤其是在患有潜在心脏并发症的患者中。由于 CQ 是溶酶体途径的抑制剂，观察到的效应可能是由于自噬抑制导致功能失调的线粒体积累所致。
