Biology 2026, 15(16), 1443; https://doi.org/10.3390/biology15161443 - 21 Aug 2026
Abstract
Age-associated mitochondrial decline reduces NAD+ availability, impairs oxidative phosphorylation (OXPHOS), and leads to accumulation of reactive oxygen species (ROS) thereby reshaping cellular metabolism. However, the regulatory logic coupling mitochondrial aging to metabolic dysregulation resulting in tumorigenic cell-fate transitions has not been modeled
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Age-associated mitochondrial decline reduces NAD+ availability, impairs oxidative phosphorylation (OXPHOS), and leads to accumulation of reactive oxygen species (ROS) thereby reshaping cellular metabolism. However, the regulatory logic coupling mitochondrial aging to metabolic dysregulation resulting in tumorigenic cell-fate transitions has not been modeled systematically. In this work, we propose a Boolean biomolecular network model of mitochondrial aging and integrate it with metabolic, cell-cycle, and apoptotic biomolecular networks comprising 94 nodes and 370 edges. We then examined how NAD+ decline, hypoxia and extracellular ROS shifts the balance between OXPHOS and glycolysis. To this end, the consolidated network model underwent dynamical analysis to elucidate the system-level outcomes as well as its molecular triggers. In particular, we investigated whether the metabolic phenotypes are reversible and how cancer-driver perturbations act in the absence of extracellular pyruvate. The model recapitulates a quiescent, OXPHOS-leaning baseline and predicts that progressive NAD+ decline lowers OXPHOS propensity (0.686 to 0.186) while raising glycolysis (0.256 to 0.426). Hypoxia and extracellular ROS synergize glycolytic and hybrid oxidative–glycolytic (W/O) states. Furthermore, these two triggers, together with elevated mitogenic signaling, give rise to a hyperproliferative, glycolytic, and apoptosis-resistant cellular state. Interesting, this state is conditionally reversible wherein receptor tyrosine kinase (RTK) inhibition redirects this cell fate toward apoptosis and collapses the W/O state. Cancer-driver analysis further indicates that, without extracellular pyruvate, VHL loss and RAS, PI3K, or AKT activation preferentially stabilizes glycolytic and hybrid states. Age-resolved TCGA-BRCA analysis provided expression-level support for the predicted remodeling, with declining OXPHOS-associated expression and concurrent OXPHOS/glycolysis activity in older Basal-like tumors. Together, our results show that mitochondrial aging is a priming condition whose tumor-permissive metabolic output is gated by microenvironmental and nutrient inputs. The model provides a novel framework for evaluating age-associated metabolic reprogramming and predicting early tumorigenic cell fates.
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(This article belongs to the Special Issue Signalling Pathways in Cancer and Disease)
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