Kramer Piet, Jung Alexander T, Hamann Andrea, Osiewacz Heinz D
Department of Biosciences, Molecular Developmental Biology, Institute of Molecular Biosciences and Cluster of Excellence Frankfurt Macromolecular Complexes, J. W. Goethe University Frankfurt, Germany.
Front Genet. 2016 Sep 14;7:165. doi: 10.3389/fgene.2016.00165. eCollection 2016.
The mitochondrial permeability transition pore plays a key role in programmed cell death and the induction of autophagy. Opening of the pore is regulated by the mitochondrial peptidyl prolyl-cis, trans-isomerase cyclophilin D (CYPD). Previously it was shown in the aging model organism Podospora anserina that PaCYPD abundance increases during aging and that PaCypD overexpressors are characterized by accelerated aging. Here, we describe a role of PaCYPD in the regulation of autophagy. We found that the accelerated aging phenotype observed in a strain overexpressing PaCypD is not metacaspase-dependent but is accompanied by an increase of general autophagy and mitophagy, the selective autophagic degradation of mitochondria. It thus is linked to what has been defined as "autophagic cell death" or "type II" programmed cell death. Moreover, we found that the previously demonstrated age-related induction of autophagy in wild-type aging depends on the presence of PaCYPD. Deletion of PaCypD leads to a decrease in autophagy in later stages of age and under paraquat-mediated oxidative stress. Finally, we report that PaCYPD is also required for mitohormesis, the beneficial effect of mild mitochondrial stress. Thus, PaCYPD plays a key role in the context-dependent regulation of pathways leading to pro-survival and pro-death effects of autophagy.
线粒体通透性转换孔在程序性细胞死亡和自噬诱导过程中发挥关键作用。该孔的开放受线粒体肽基脯氨酰顺反异构酶亲环蛋白D（CYPD）调控。先前在衰老模式生物嗜热栖热放线菌中发现，PaCYPD的丰度在衰老过程中增加，且PaCypD过表达菌株的特征是衰老加速。在此，我们描述了PaCYPD在自噬调控中的作用。我们发现，在过表达PaCypD的菌株中观察到的加速衰老表型不依赖于metacaspase，但伴随着一般自噬和线粒体自噬（线粒体的选择性自噬降解）的增加。因此，它与被定义为“自噬性细胞死亡”或“II型”程序性细胞死亡相关。此外，我们发现先前证明的野生型衰老过程中与年龄相关的自噬诱导依赖于PaCYPD的存在。缺失PaCypD会导致衰老后期以及百草枯介导的氧化应激下自噬减少。最后，我们报告PaCYPD也是线粒体应激反应（轻度线粒体应激的有益作用）所必需的。因此，PaCYPD在导致自噬的促生存和促死亡效应的途径的上下文依赖性调控中起关键作用。
