Sizek2023 - Mitochondrial Dysfunction-Associated Senescence (MiDAS) with cell cycle and apoptosis

This 133-node Boolean regulatory network model reproduces mitochondrial dynamics during cell cycle progression (hyper-fusion at the G1/S boundary, fission in mitosis), apoptosis (fission and dysfunction) and glucose starvation (reversible hyper-fusion), as well as MiDAS in response to SIRT3 knockdown or oxidative stress and the protective role of NAD+ or external pyruvate. These features are in addition to the cell cycle-related phenotypes reproduced by the Sizek et al model that served as our starting point. Testable predictions (new): a) In cell lines with low basal p21 expression known to pre-commit to the next division in early mitosis of their current cycle, a subset of cells respond to glucose withdrawal by arresting with 4N DNA content but losing their internal G2 state (i.e. Cyclin A/B expression), and undergo endo-reduplication upon glucose re-exposure. b) In a subset of glucose-starved cells that pass the G2/M checkpoint with hyperfused mitochondria, mitotic fragmentation can be sufficiently delayed to cause spindle assembly defects and mitotic catastrophe. c) Quiescent cells are less susceptible to ROS-induced MiDAS due to FoxO-mediated PINK1 expression, which blocks MFN1/2 from inducing hyperfusion. d) Boosting NAD+ levels in MiDAS cells that have not yet established deep senescence (2-3 days post induction) can reverse their fate.