Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Cell Metab. 2021 Mar 2;33(3):598-614.e7. doi: 10.1016/j.cmet.2021.01.013. Epub 2021 Feb 15.
The architecture of cristae provides a spatial mitochondrial organization that contains functional respiratory complexes. Several protein components including OPA1 and MICOS complex subunits organize cristae structure, but upstream regulatory mechanisms are largely unknown. Here, in vivo and in vitro reconstitution experiments show that the endoplasmic reticulum (ER) kinase PERK promotes cristae formation by increasing TOM70-assisted mitochondrial import of MIC19, a critical subunit of the MICOS complex. Cold stress or β-adrenergic stimulation activates PERK that phosphorylates O-linked N-acetylglucosamine transferase (OGT). Phosphorylated OGT glycosylates TOM70 on Ser94, enhancing MIC19 protein import into mitochondria and promoting cristae formation and respiration. In addition, PERK-activated OGT O-GlcNAcylates and attenuates CK2α activity, which mediates TOM70 Ser94 phosphorylation and decreases MIC19 mitochondrial protein import. We have identified a cold-stress inter-organelle PERK-OGT-TOM70 axis that increases cell respiration through mitochondrial protein import and subsequent cristae formation. These studies have significant implications in cellular bioenergetics and adaptations to stress conditions.
嵴的结构提供了一种空间线粒体组织，其中包含有功能的呼吸复合物。几种蛋白质成分，包括 OPA1 和 MICOS 复合物亚基，组织嵴结构，但上游调节机制在很大程度上是未知的。在这里，体内和体外重组实验表明，内质网（ER）激酶 PERK 通过增加 TOM70 辅助的 MIC19 的线粒体导入来促进嵴的形成，MIC19 是 MICOS 复合物的关键亚基。冷应激或β-肾上腺素能刺激激活 PERK，磷酸化 O-连接的 N-乙酰葡萄糖胺转移酶（OGT）。磷酸化的 OGT 将糖基化转移酶 TOM70 上的丝氨酸 94 上，增强 MIC19 蛋白导入线粒体，并促进嵴的形成和呼吸。此外，PERK 激活的 OGT O-糖基化并减弱 CK2α 活性，该活性介导 TOM70 丝氨酸 94 的磷酸化，并减少 MIC19 线粒体蛋白导入。我们已经确定了冷应激细胞器间 PERK-OGT-TOM70 轴，该轴通过线粒体蛋白导入和随后的嵴形成增加细胞呼吸。这些研究在细胞生物能量学和对应激条件的适应方面具有重要意义。
