The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Jinan University, Dongguan, Guangdong, 523067, China.
The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, Guangdong, 510632, China.
Nat Commun. 2023 Oct 4;14(1):6201. doi: 10.1038/s41467-023-41757-x.
Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice.
核酸内切酶 G（ENDOG）是一种核编码的线粒体跨膜间隙蛋白，众所周知，它在细胞凋亡过程中会被转运到细胞核内。最近的研究表明，ENDOG 可能进入线粒体基质，以调节线粒体基因组的切割和复制。然而，关于细胞质中 ENDOG 的作用知之甚少。我们之前的工作表明，细胞质中的 ENDOG 可以与 14-3-3γ 竞争结合，从而释放 TSC2 以抑制 mTORC1 信号并诱导自噬。在这里，我们证明细胞质中的 ENDOG 也可以将 Rictor 从 14-3-3γ 上释放出来，从而激活 mTORC2-AKT-ACLY 轴，导致乙酰辅酶 A 的产生。重要的是，我们观察到 ENDOG 可以易位到内质网，与 Bip 结合，并释放 IRE1a/PERK 以激活内质网应激反应，促进脂质合成。总之，我们证明了 ENDOG 的缺失会抑制乙酰辅酶 A 的产生和脂质合成，并减轻内质网应激，最终减轻高脂饮食诱导的雌性小鼠非酒精性脂肪性肝病。
