Functional restoration of lysosomes and mitochondria through modulation of AKT activity ameliorates senescence
Myeong Uk Kuk, Haneur Lee, Eun Seon Song, Yun Haeng Lee, Ji Yun Park, Ji Yun Park, Subin Jeong, Hyung Wook Kwon, Youngjoo Byun, Sang Chul Park, Joon Tae Park, Joon Tae Park
Abstract
Senescence is a phenomenon defined by alterations in cellular organelles and is the primary cause of aging and aging-related diseases. Recent studies have shown that oncogene-induced senescence is driven by activation of serine/threonine protein kinases (AKT1, AKT2 and AKT3). In this study, we evaluated twelve AKT inhibitors and revealed GDC0068 as a potential agent to ameliorate senescence. Senescence-ameliorating effect was evident from the finding that GDC0068 yielded lysosomal functional recovery as observed by reduction in lysosomal mass and induction in autophagic flux. Furthermore, GDC0068-mediated restoration of lysosomal function activated the removal of dysfunctional mitochondria, resulting in restoration of mitochondrial function. Together, our findings revealed a unique mechanism by which senescence is recovered by functional restoration of lysosomes and mitochondria through modulation of AKT activity.