College of Pharmacy, Chonnam National University, 77, Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.
Department of Bioengineering and Biotechnology, College of Engineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, 61186, Gwangju, Republic of Korea.
Arch Pharm Res. 2022 Oct;45(10):731-742. doi: 10.1007/s12272-022-01412-3. Epub 2022 Oct 28.
Autophagy is a complex degradation pathway through which damaged or dysfunctional proteins and organelles are removed. Its pharmacological modulators have been extensively used in a wide range of basic research and preclinical studies. However, the effects of these inhibitors on metabolism, in addition to autophagy inhibition, are not fully elucidated. Chloroquine is a clinically relevant compound that inhibits autophagy by preventing the fusion of autophagosomes with lysosomes. In this study, we aimed to examine the effect of chloroquine on mitochondrial quality control and respiratory function by utilizing 3T3-L1 mouse adipocytes treated with chloroquine at various time points. We found that chloroquine could disturb genes related to mitochondrial fission, biogenesis, and mitophagy, leading to mitochondrial DNA damage. Although the inhibition of autophagy by chloroquine resulted in an increased prohibitin expression, respiratory function was downregulated in a time-dependent manner. Moreover, chloroquine treatment induced oxidative stress, apoptosis, and metabolic dysregulation. These data demonstrated that chloroquine significantly affected mitochondrial respiratory function and metabolism, which was consistent with impaired mitochondrial quality associated with autophagy inhibition.
自噬是一种复杂的降解途径，通过该途径可以清除受损或功能失调的蛋白质和细胞器。其药理学调节剂已广泛应用于广泛的基础研究和临床前研究。然而，这些抑制剂除了抑制自噬之外，对代谢的影响尚未完全阐明。氯喹是一种临床相关的化合物，通过阻止自噬体与溶酶体融合来抑制自噬。在这项研究中，我们旨在通过使用在不同时间点用氯喹处理的 3T3-L1 小鼠脂肪细胞，研究氯喹对线粒体质量控制和呼吸功能的影响。我们发现氯喹可以干扰与线粒体分裂、生物发生和线粒体自噬相关的基因，导致线粒体 DNA 损伤。虽然氯喹对自噬的抑制导致抑素表达增加，但呼吸功能呈时间依赖性下调。此外，氯喹处理诱导氧化应激、细胞凋亡和代谢失调。这些数据表明，氯喹显著影响线粒体呼吸功能和代谢，这与自噬抑制相关的线粒体质量受损一致。
