Research Paper Volume 12, Issue 8 pp 6700—6732
Mitochondrial nucleoid remodeling and biogenesis are regulated by the p53-p21WAF1-PKCζ pathway in p16INK4a-silenced cells
Figure 7. Signal transduction pathways regulate mitochondrial nucleoid remodeling and biogenesis in senescent human fibroblasts. (A) Activation of p53-p21WAF1 or silencing of p16INK4a-pRB induces mitochondrial nucleoid remodeling and biogenesis via the PKCζ-LKB1(STK11)-AMPK-PGC-1α-NRF1-TFAM pathway in senescent human fibroblasts. Induction of p21WAF1 and silencing of p16INK4a, together with reactive oxygen species (ROS) accumulation and PDK1, significantly activated PKCζ, which might explain the delayed senescence in fs-HDF compared to WI-38 cells. (B) Ingenuity pathway analysis (IPA) using RNA-sequencing data. Red and pink indicate increased expression; green shows decreased expression. Arrow indicates signal activation; solid line for direct interaction, dotted line shows possible interaction. Note significant activation of PKCζ and PGC-1α (PPARGC1A), and mild activation of AMPK. Increased expression levels of TP53 and CDKN1A (p21WAF1) were followed by senescence of human fibroblasts and biogenesis of the mitochondrial complex-I, -IV, and -V subunits.