Inhibition of mitochondrial OMA1 ameliorates osteosarcoma tumorigenesis.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-11-01 DOI:10.1038/s41419-024-07127-1
Lingyan Chen, Dejian Chen, Yiming Pan, Yimei Mo, Biyu Lai, Huiguang Chen, Da-Wei Zhang, Xiao-Dan Xia
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Abstract

OMA1 is an ATP-independent zinc metalloprotease essential for maintaining mitochondrial homeostasis and plays a vital role in tumorigenesis. Depending on the type of cancer, a decrease in OMA1 expression has been linked to a varying prognosis for patients. The role of OMA1 in human osteosarcoma (OS), one of the most prevalent malignant bone tumors, remains elusive. Here, we observed elevated OMA1 expression in OS tumor tissues from four patients with advanced OS. Knockout of OMA1 in OS cells significantly reduces OS tumor weight and size, and lung metastatic nodules in BALB/c nude mice. Immunohistochemistry analysis showed a significant decrease in Ki67 and an increase in Cleaved-caspase 3 in OMA1 knockout tumor samples. Mechanistically, we found that OMA1 deficiency increases the levels of PINK1 and Parkin and consequently induces excessive mitophagy, leading to increased apoptosis and reduced cell proliferation and invasion in OS cells. Specifically, OMA1 deficiency reduces the amount of cytosolic p53 and p53-associated cytosolic Parkin but increases mitochondrial p53, which may lead to enhanced apoptosis. Regarding the effect on cell proliferation and invasion, loss of OMA1 reduces mitochondrial ROS levels and increases cytosolic glycogen synthase kinase 3β (GSK3β) levels, thereby increasing interaction between GSK3β and β-catenin and then reducing cytosolic and nuclear β-catenin. This contributes to reduced cell proliferation and migration in OMA1-deficient cells. Moreover, we found that ciclopirox (CPX), an antifungal drug, induces OMA1 self-cleavage and L-OMA1 degradation in cultured OS cells. CPX also reduces tumor development of control OS cells but not OMA1-deficient OS cells in mice. These findings strongly support the important role of OMA1 in OS tumorigenesis and suggest that OMA1 may be a valuable prognostic marker and a promising therapeutic target for OS.

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抑制线粒体 OMA1 可改善骨肉瘤的肿瘤发生。
OMA1 是一种不依赖于 ATP 的锌金属蛋白酶,对维持线粒体平衡至关重要,并在肿瘤发生过程中发挥着重要作用。根据癌症类型的不同,OMA1 表达的减少与患者不同的预后有关。OMA1在人类骨肉瘤(OS)--最常见的恶性骨肿瘤之一--中的作用仍然难以捉摸。在这里,我们观察到四名晚期骨肉瘤患者的骨肉瘤组织中 OMA1 表达升高。敲除 OS 细胞中的 OMA1 能显著减轻 OS 肿瘤的重量和大小,并减少 BALB/c 裸鼠肺转移结节。免疫组化分析表明,在OMA1基因敲除的肿瘤样本中,Ki67明显降低,Cleaved-caspase 3增加。从机理上讲,我们发现OMA1的缺乏会增加PINK1和Parkin的水平,从而诱导过度的有丝分裂,导致OS细胞凋亡增加、细胞增殖和侵袭减少。具体来说,OMA1缺乏会降低细胞膜p53和与p53相关的细胞膜Parkin的含量,但会增加线粒体p53的含量,这可能会导致细胞凋亡增强。关于对细胞增殖和侵袭的影响,OMA1 的缺失会降低线粒体 ROS 水平,增加细胞olic糖原合酶激酶 3β(GSK3β)水平,从而增加 GSK3β 和 β-catenin 之间的相互作用,进而减少细胞olic 和细胞核中的β-catenin。这导致 OMA1 缺陷细胞的细胞增殖和迁移能力降低。此外,我们还发现抗真菌药物环吡酮胺(CPX)可诱导培养的OS细胞中的OMA1自我裂解和L-OMA1降解。CPX还能减少对照OS细胞的肿瘤发生,但不能减少小鼠体内OMA1缺陷OS细胞的肿瘤发生。这些发现有力地证明了OMA1在OS肿瘤发生过程中的重要作用,并表明OMA1可能是一种有价值的预后标志物,也是一种有希望成为OS治疗靶点的药物。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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