Howard Hughes Medical Institute and Molecular Radiation Oncology, Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
Mol Cell. 2010 Dec 22;40(6):893-904. doi: 10.1016/j.molcel.2010.12.013.
Genetic deletion of the mitochondrial deacetylase sirtuin-3 (Sirt3) results in increased mitochondrial superoxide, a tumor-permissive environment, and mammary tumor development. MnSOD contains a nutrient- and ionizing radiation (IR)-dependent reversible acetyl-lysine that is hyperacetylated in Sirt3⁻/⁻ livers at 3 months of age. Livers of Sirt3⁻/⁻ mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Reintroduction of wild-type but not deacetylation null Sirt3 into Sirt3⁻/⁻ MEFs deacetylated lysine and restored MnSOD activity. Site-directed mutagenesis of MnSOD lysine 122 to an arginine, mimicking deacetylation (lenti-MnSOD(K122-R)), increased MnSOD activity when expressed in MnSOD⁻/⁻ MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3⁻/⁻ MEFs with lenti-MnSOD(K122-R) inhibited in vitro immortalization by an oncogene (Ras), inhibited IR-induced genomic instability, and decreased mitochondrial superoxide. Finally, IR was unable to induce MnSOD deacetylation or activity in Sirt3⁻/⁻ livers, and these irradiated livers displayed significant IR-induced cell damage and microvacuolization in their hepatocytes.
线粒体脱乙酰酶 Sirtuin-3（Sirt3）的基因缺失导致线粒体超氧化物增加，形成有利于肿瘤生长的环境，并促进乳腺肿瘤的发展。MnSOD 含有一个受营养物质和电离辐射（IR）影响的可逆乙酰化赖氨酸，在 3 个月大的 Sirt3⁻/⁻肝脏中，该赖氨酸被高度乙酰化。与野生型肝脏相比，Sirt3⁻/⁻小鼠肝脏中的 MnSOD 活性降低，但免疫反应性蛋白不变。将野生型而非去乙酰化缺陷型 Sirt3 重新导入 Sirt3⁻/⁻ MEF 中，可使赖氨酸去乙酰化并恢复 MnSOD 活性。MnSOD 赖氨酸 122 突变为精氨酸的定点突变（lenti-MnSOD（K122-R）），在 MnSOD⁻/⁻ MEF 中表达时增加了 MnSOD 活性，表明乙酰化直接调节其功能。此外，用 lenti-MnSOD（K122-R）感染 Sirt3⁻/⁻ MEF 可抑制致癌基因（Ras）诱导的体外永生化、抑制 IR 诱导的基因组不稳定性，并减少线粒体超氧化物。最后，IR 无法诱导 Sirt3⁻/⁻肝脏中的 MnSOD 去乙酰化或活性，而这些受照射的肝脏在其肝细胞中显示出明显的 IR 诱导的细胞损伤和微空泡化。
