Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Erzsébet Ravasz Regan

PROVIDER: MODEL2312140001 | BioModels | 2024-08-26

REPOSITORIES: BioModels

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			Action	DRS
	MODEL2312140001?filename=MiDAS_Cell_Cycle_Arrests_Apoptosis.dmms	Other
	MODEL2312140001?filename=MiDAS_Cell_Cycle_Arrests_Apoptosis_Fine.XML	Xml
	MODEL2312140001?filename=MiDAS_Cell_Cycle_Arrests_Apoptosis_Fine.booleannet	Other
	MODEL2312140001?filename=MiDAS__Main_Figures.vex	Other
	MODEL2312140001?filename=MiDAS__SM_Figures.vex	Other

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Publications

Unlocking mitochondrial dysfunction-associated senescence (MiDAS) with NAD<sup>+</sup> - A Boolean model of mitochondrial dynamics and cell cycle control.

Sizek Herbert H Deritei Dávid D Fleig Katherine K Harris Marlayna M Regan Peter L PL Glass Kimberly K Regan Erzsébet Ravasz ER

Translational oncology 20240819

The steady accumulation of senescent cells with aging creates tissue environments that aid cancer evolution. Aging cell states are highly heterogeneous. 'Deep senescent' cells rely on healthy mitochondria to fuel a strong proinflammatory secretome, including cytokines, growth and transforming signals. Yet, the physiological triggers of senescence such as reactive oxygen species (ROS) can also trigger mitochondrial dysfunction, and sufficient energy deficit to alter their secretome and cause chro ...[more]

PMID: 39163758

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