PRPF8在低氧诱导的线粒体自噬中的作用及其调控机制研究

Aged and damaged mitochondria can be selectively degraded by specific autophagic elimination, termed mitophagy. Defects in mitophagy have been increasingly linked to several diseases including neurodegenerative diseases, metabolic diseases and other aging-related diseases. However, the molecular mechanisms of mitophagy is not fully understood. Here, we identify the pre-mRNA processing factor 8, a core component of spliceosome, as an essential mediator in hypoxia-induced mitophagy from an RNAi screen based on a fluorescent mitophagy reporter mt-Keima. Knockdown of PRPF8 by different siRNA significantly impairs the hypoxia-induced mitophagosome formation and subsequent mitochondrial clearance. Furthermore, knockdown of PRPF8 inhibits the hypoxia-induced increase of ULK1 mRNA level, which suggested that PRPF8 might regulate mitophagy process through modulating the mRNA splicing of ULK1. Based on these observations, we plan to study how spliceosome regulates hypoxia-induced mitophagy.. And, we will also study whether the defect in mitophagy is related to PRPF8 mutation associated-autosomal dominant retinitis pigmentosa (adRP). Thus, our study will shed light on the mechanisms of mitophagy and its role in human health and diseases.

选择性清除衰老和受损线粒体的过程称为线粒体自噬。许多研究表明，线粒体自噬异常与多种人类疾病密切相关，如神经退行性疾病和代谢疾病等。然而，线粒体自噬的分子调控机制尚不完全清楚。本研究利用mt-Keima荧光报告系统，通过siRNA文库筛选，鉴定到新的低氧诱导线粒体自噬的调控分子，剪切小体的核心组分—PRPF8。我们的研究发现，敲低PRPF8的表达，显著抑制低氧诱导的线粒体自噬小体的形成及线粒体清除过程。进一步的研究发现，敲低PRPF8抑制低氧诱导的ULK1 mRNA表达上调，提示PRPF8可能通过调控ULK1 mRNA剪切参与线粒体自噬。本项目将以PRPF8为切入点，深入探讨剪切因子对低氧诱导线粒体自噬的调控作用及其具体机制。同时，将深入研究PRPF8突变相关的视网膜色素变性病是否与线粒体自噬的异常有关。本项目的实施，将有助于加深人们对线粒体自噬调控机制及其与人类健康和疾病关系的认识。