SummaryMitochondria are semi-autonomous eukaryotic organelles, that participate in energy production and metabolism, making mitochondrial quality control crucial. As most mitochondrial proteins are encoded by nuclear genes, quality control depends on proper mitochondria-nucleus communication, designated mitochondrial retrograde signaling. Early studies focused on retrograde signaling participants and specific gene knockouts. However, mitochondrial signal modulation remains elusive. Using yeast, we simulated signal propagation following mitochondrial damage and proposed a mathematical model based on enzyme kinetics and ordinary differential equations. Mitochondrial retrograde signaling decisions were described by a Boolean model. Dynamics were analyzed through an ordinary differential equation-based model and extended to evaluate the model response to noisy damage signals. Simulation revealed localized protein concentration dynamics, including waveforms, frequency response, and robustness under noise. Retrograde signaling is bistable with three localized steady states, while increased damage compromises robustness. We elucidated mitochondrial retrograde signaling, providing a basis for drug design against yeast and fungi.
Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics
