Ophiobolin A Covalently Targets Mitochondrial Complex IV Leading to Metabolic Collapse in Cancer Cells,ACS Chemical Biology

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Ophiobolin A Covalently Targets Mitochondrial Complex IV Leading to Metabolic Collapse in Cancer Cells
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2024-05-13 , DOI: 10.1021/acschembio.4c00064
Flor A Gowans _{1,

2,

3,

4,

5} , Danny Q Thach _{2,

3} , Zhouyang Zhu _{2,

3} , Yangzhi Wang _{2,

3,

4,

6} , Belen E Altamirano Poblano _{2,

3,

4,

6} , Dustin Dovala _{3,

7} , John A Tallarico _{3,

8} , Jeffrey M McKenna _{3,

6} , Markus Schirle _{3,

8} , Thomas J Maimone _{2,

3} , Daniel K Nomura _{1,

2,

3,

4,

5}

Affiliation

Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anticancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of the OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets: lysine-72 of cytochrome c oxidase subunit 5A (COX5A) and cysteine-53 of mitochondrial hypoxia induced gene 1 domain family member 2A (HIGD2A). These two subunit proteins are part of complex IV (cytochrome C oxidase) within the electron transport chain and contributed significantly to the antiproliferative activity of OPA. OPA activated mitochondrial respiration in a COX5A- and HIGD2A-dependent manner, leading to an initial spike in mitochondrial ATP and heightened mitochondrial oxidative stress. OPA compromised mitochondrial membrane potential, ultimately leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anticancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death.

中文翻译：

Ophiobolin A 共价靶向线粒体复合物 IV，导致癌细胞代谢崩溃

Ophiobolin A (OPA) 是一种二倍萜类真菌天然产物，具有广泛的抗癌活性。虽然 OPA 拥有多个亲电子部分，可以与蛋白质上的亲核氨基酸发生共价反应，但 OPA 的蛋白质组范围目标和机制在许多情况下仍然知之甚少。在这项研究中，我们使用共价化学蛋白质组平台来绘制高度敏感的肺癌细胞系中 OPA 的蛋白质组范围反应性。在 OPA 参与的几种蛋白质中，我们重点关注两个靶标：细胞色素 c 氧化酶亚基 5A (COX5A) 的赖氨酸-72 和线粒体缺氧诱导基因 1 结构域家族成员 2A (HIGD2A) 的半胱氨酸-53。这两个亚基蛋白是电子传递链内复杂 IV（细胞色素 C 氧化酶）的一部分，对 OPA 的抗增殖活性有显着贡献。 OPA 以 COX5A 和 HIGD2A 依赖性方式激活线粒体呼吸，导致线粒体 ATP 初始峰值并加剧线粒体氧化应激。 OPA 损害线粒体膜电位，最终导致 ATP 耗尽。我们使用化学蛋白质组学策略发现了 OPA 的独特抗癌机制，通过激活复合物 IV 导致线粒体能量受损和快速细胞死亡。

更新日期：2024-05-13

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