Department of Medicine, Diabetes Unit, and Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School , Boston , MA , USA.
Autophagy. 2019 Oct;15(10):1852-1853. doi: 10.1080/15548627.2019.1644077. Epub 2019 Jul 18.
A wide variety of genetic, pharmacological and nutrient manipulations that extend lifespan in model organisms do so in a manner dependent upon increased autophagic flux. However, our recent findings suggest that when mitochondrial membrane integrity is compromised, macroautophagy/autophagy can be detrimental. In lacking the serine/threonine kinase mechanistic target of rapamycin kinase complex 2 and its downstream effector SGK-1 (Serum- and Glucocorticoid-inducible Kinase homolog), lifespan is shortened in spite of increased levels of autophagy, whereas reducing autophagy restores normal lifespan. This is due to a concomitant defect in mitochondrial permeability in mutants defective in either SGK-1 or mechanistic target of rapamycin kinase complex 2, attributable to increased VDAC-1 (VDAC Voltage Dependent Anion Channel homolog) protein level. More generally, we find that induction of mitochondrial permeability reverses each and every tested paradigm of autophagy-dependent lifespan extension and, further, exacerbates ischemia-reperfusion injury. In this punctum, we discuss our finding that autophagy with increased mitochondrial permeability is a detrimental combination conserved from nematode to mammals.
多种遗传、药理学和营养干预手段可延长模型生物的寿命，其作用方式依赖于自噬通量的增加。然而，我们最近的发现表明，当线粒体膜完整性受到损害时，巨自噬/自噬可能是有害的。在缺乏丝氨酸/苏氨酸激酶雷帕霉素机制靶蛋白激酶复合物 2 及其下游效应物 SGK-1（血清和糖皮质激素诱导的激酶同源物）的情况下，尽管自噬水平增加，但寿命缩短，而减少自噬则恢复正常寿命。这是由于在 SGK-1 或雷帕霉素机制靶蛋白激酶复合物 2 缺陷的突变体中同时存在线粒体通透性缺陷，这归因于 VDAC-1（电压依赖性阴离子通道同源物）蛋白水平的增加。更普遍的是，我们发现诱导线粒体通透性逆转了每一个经过测试的自噬依赖性寿命延长范例，并且进一步加剧了缺血再灌注损伤。在这一点上，我们讨论了我们的发现，即增加的线粒体通透性的自噬是一种从线虫到哺乳动物都保守的有害组合。
