Functional restoration of lysosomes and mitochondria through modulation of AKT activity ameliorates senescence

• Published in: Experimental gerontology 2023-03, Vol.173, p.112091-112091, Article 112091
• Main Authors: Kuk, Myeong Uk, Lee, Haneur, Song, Eun Seon, Lee, Yun Haeng, Park, Ji Yun, Jeong, Subin, Kwon, Hyung Wook, Byun, Youngjoo, Park, Sang Chul, Park, Joon Tae
• Format: Article
• Language: English
• Subjects: AKT; Autophagy; Cellular Senescence; GDC0068; Lysosome; Lysosomes - metabolism; Mitochondria; Mitochondria - metabolism; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Senescence amelioration
• ISSN: 0531-5565; 1873-6815
• DOI: 10.1016/j.exger.2023.112091

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. •AKT inhibition yielded lysosomal recovery as observed by reduction in lysosomal mass and induction in autophagic flux.•AKT inhibition-mediated restoration of lysosomal function promoted restoration of mitochondrial function.•Functional restoration of lysosomes and mitochondria through AKT inhibition promoted senescence amelioration.