Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Mol Cell Biol. 2014 Apr;34(8):1427-37. doi: 10.1128/MCB.01021-13. Epub 2014 Feb 3.
The tumorous imaginal disc 1 (TID1) protein localizes mainly to the mitochondrial compartment, wherein its function remains largely unknown. Here we report that TID1 regulates the steady-state homogeneity of the mitochondrial membrane potential (Δψ) and maintains the integrity of mitochondrial DNA (mtDNA). Silencing of TID1 with RNA interference leads to changes in the distribution of Δψ along the mitochondrial network, characterized by an increase in Δψ in focal regions. This effect can be rescued by ectopic expression of a TID1 construct with an intact J domain. Chronic treatment with a low dose of oligomycin, an inhibitor of F1Fo ATP synthase, decreases the cellular ATP content and phenocopies TID1 loss of function, indicating a connection between the disruption of mitochondrial bioenergetics and hyperpolarization. Prolonged silencing of TID1 or low-dose oligomycin treatment leads to the loss of mtDNA and the consequent inhibition of oxygen consumption. Biochemical and colocalization data indicate that complex I aggregation underlies the focal accumulation of Δψ in TID1-silenced cells. Given that TID1 is proposed to function as a cochaperone, these data show that TID1 prevents complex I aggregation and support the existence of a TID1-mediated stress response to ATP synthase inhibition.
肿瘤样盘 1（TID1）蛋白主要定位于线粒体区室，其功能尚不清楚。在这里，我们报告 TID1 调节线粒体膜电位（Δψ）的稳态均一性，并维持线粒体 DNA（mtDNA）的完整性。用 RNA 干扰沉默 TID1 会导致 Δψ 在沿线粒体网络的分布发生变化，其特征是在焦点区域 Δψ 增加。这种效应可以通过异位表达具有完整 J 结构域的 TID1 构建体来挽救。低剂量寡霉素（F1Fo ATP 合酶抑制剂）的慢性处理会降低细胞内的 ATP 含量，并模拟 TID1 功能丧失的表型，表明线粒体生物能量学的破坏与超极化之间存在联系。TID1 的长期沉默或低剂量寡霉素处理会导致 mtDNA 丢失，进而抑制耗氧量。生化和共定位数据表明，复合物 I 聚集是 TID1 沉默细胞中 Δψ 焦点积累的基础。鉴于 TID1 被提议作为共伴侣发挥作用，这些数据表明 TID1 可防止复合物 I 聚集，并支持存在 TID1 介导的对 ATP 合酶抑制的应激反应。
