The steady accumulation of senescent cells with aging creates tissue environments that aid cancer evolution. The secretome of senescent cells promotes chronic inflammation, contains growth and transforming signals, and causes chronic oxidative stress. The latter is primarily due to dysfunctional mitochondria often seen in senescent cells. Aging cell states are highly heterogeneous. 'Deep senescent' cells rely on healthy mitochondria to fuel a strong proinflammatory secretome. In parallel, the triggers of deep senescence also generate cells with mitochondrial dysfunction, and sufficient energy deficit to alter their secretome - a state termed Mitochondrial Dysfunction-Associated Senescence (MiDAS). Here we offer a mechanistic explanation for the molecular processes leading to MiDAS. To do this we have built a Boolean regulatory network model able to reproduce 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. Our model also recapitulates the protective role of NAD + and external pyruvate. We offer testable predictions about the growth factor- and glucose-dependence of MiDAS and its reversibility at different stages of reactive oxygen species (ROS)-induced senescence. Our model opens the door to modeling distinct stages of DNA-damage induced senescence, the relationship between senescence and epithelial-to-mesenchymal transition in cancer and building multiscale models of tissue aging.
Highlights: Boolean regulatory network model reproduces mitochondrial dynamics during cell cycle progression, apoptosis, and glucose starvation. Model offers a mechanistic explanation for the positive feedback loop that locks in Mitochondrial Dysfunction-Associated Senescence (MiDAS), involving autophagy-resistant hyperfused but dysfunctional mitochondria. Model reproduces ROS-mediated mitochondrial dysfunction and suggests that MiDAS is part of the early phase of damage-induced senescence. Model predicts that cancer-driving mutations that bypass the G1/S checkpoint generally increase the incidence of MiDAS, with the notable exception of p53 loss.