Department of Molecular Biology and Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Biology, MIT, Cambridge, MA 02139, USA.
Mol Cell. 2021 May 6;81(9):1905-1919.e12. doi: 10.1016/j.molcel.2021.02.033. Epub 2021 Apr 13.
Oxidative phosphorylation (OXPHOS) and glycolysis are the two major pathways for ATP production. The reliance on each varies across tissues and cell states, and can influence susceptibility to disease. At present, the full set of molecular mechanisms governing the relative expression and balance of these two pathways is unknown. Here, we focus on genes whose loss leads to an increase in OXPHOS activity. Unexpectedly, this class of genes is enriched for components of the pre-mRNA splicing machinery, in particular for subunits of the U1 snRNP. Among them, we show that LUC7L2 represses OXPHOS and promotes glycolysis by multiple mechanisms, including (1) splicing of the glycolytic enzyme PFKM to suppress glycogen synthesis, (2) splicing of the cystine/glutamate antiporter SLC7A11 (xCT) to suppress glutamate oxidation, and (3) secondary repression of mitochondrial respiratory supercomplex formation. Our results connect LUC7L2 expression and, more generally, the U1 snRNP to cellular energy metabolism.
氧化磷酸化（OXPHOS）和糖酵解是产生 ATP 的两种主要途径。每种途径的依赖程度因组织和细胞状态而异，并可能影响对疾病的易感性。目前，尚不清楚控制这两种途径相对表达和平衡的全套分子机制。在这里，我们专注于那些导致 OXPHOS 活性增加的基因丢失。出乎意料的是，这一类基因富含前体 mRNA 剪接机制的组件，特别是 U1 snRNP 的亚基。在这些基因中，我们表明 LUC7L2 通过多种机制抑制 OXPHOS 并促进糖酵解，包括（1）糖酵解酶 PFKM 的剪接以抑制糖原合成，（2）胱氨酸/谷氨酸载体 SLC7A11（xCT）的剪接以抑制谷氨酸氧化，以及（3）对线粒体呼吸超级复合物形成的二级抑制。我们的结果将 LUC7L2 的表达以及更普遍的 U1 snRNP 与细胞能量代谢联系起来。
