生物
PPARGC1A型
粒体自噬
线粒体生物发生
凝集素
细胞生物学
线粒体
自噬
生物发生
细胞器生物发生
癌症
细胞
尼泊尔卢比1
癌症研究
遗传学
细胞凋亡
辅活化剂
基因
转录因子
作者
Prakash Priyadarshi Praharaj,Srimanta Patra,Amruta Singh,Debasna Pritimanjari Panigrahi,Hwa-Young Lee,Mohammad Fazlul Kabir,Muhammad Kamal Hossain,Samir Kumar Patra,Birija Sankar Patro,Shankargouda Patil,Daniel J. Klionsky,Han-Jung Chae,Sujit K. Bhutia
出处
期刊:Autophagy
[Informa]
日期:2024-03-06
卷期号:: 1-25
标识
DOI:10.1080/15548627.2024.2309904
摘要
Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU acts as an adaptor protein that coordinately interacts with BAX and LC3 recruiting autophagic machinery around damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes resulting in reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (siPPARGC1A) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer.
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