PDF(Pubmed)
Abstract：
Mitochondrial intracrines are extracellular signaling proteins, targeted to the mitochondria. The pathway for mitochondrial targeting of mitochondrial intracrines and actions in the mitochondria remains unknown. Megalin/LRP2 mediates the uptake of vitamins and proteins, and is critical for clearance of amyloid-β protein from the brain. Megalin mutations underlie the pathogenesis of Donnai-Barrow and Lowe syndromes, characterized by brain defects and kidney dysfunction; megalin was not previously known to reside in the mitochondria. Here, we show megalin is present in the mitochondria and associates with mitochondrial anti-oxidant proteins SIRT3 and stanniocalcin-1 (STC1). Megalin shuttles extracellularly-applied STC1, angiotensin II and TGF-β to the mitochondria through the retrograde early endosome-to-Golgi transport pathway and Rab32. Megalin knockout in cultured cells impairs glycolytic and respiratory capacities. Thus, megalin is critical for mitochondrial biology; mitochondrial intracrine signaling is a continuum of the retrograde early endosome-to-Golgi-Rab32 pathway and defects in this pathway may underlie disease processes in many systems.
摘要：
线粒体内是细胞外信号蛋白，靶向线粒体.线粒体内的线粒体靶向和线粒体中的作用的途径仍然未知。Megalin/LRP2介导维生素和蛋白质的摄取，并且对于从大脑中清除淀粉样β蛋白至关重要。Megalin突变是Donnai-Barrow和Lowe综合征发病机理的基础，以脑缺陷和肾功能障碍为特征；megalin以前未知存在于线粒体中。这里,我们显示megalin存在于线粒体中，并与线粒体抗氧化蛋白SIRT3和stiniocalcin-1（STC1）相关。Megalin通过逆行的早期内体到高尔基体的转运途径和Rab32将细胞外的STC1，血管紧张素II和TGF-β应用于线粒体。培养细胞中的Megalin敲除会损害糖酵解和呼吸能力。因此，megalin对于线粒体生物学至关重要；线粒体内分泌素信号是逆行早期内体到高尔基体-Rab32通路的连续体，该通路的缺陷可能是许多系统中疾病过程的基础。
