# How Mitochondrial Signaling Games May Shape and Stabilize the Nuclear-Mitochondrial Symbiosis

## TL;DR

This paper uses a game theory model to explain how the long-term cooperation between the nucleus and mitochondria in cells may have formed and remained stable over billions of years.

## Contribution

The paper introduces a novel biomolecular signaling games model to explain the establishment and maintenance of nuclear-mitochondrial cooperation.

## Key findings

- Cellularization stabilizes efficient sender-receiver interactions in the nuclear-mitochondrial relationship.
- Extracellular environments fail to maintain efficient signaling due to sender indifference to receiver effects.
- The model has implications for mitochondrial medicine and speculative ideas about human-AI symbiosis.

## Abstract

We introduce a biomolecular signaling games model of cell-mitochondrion interaction, that helps to explain how cooperation between the two may have become established and maintained.

The eukaryotic lineage has enjoyed a long-term “stable” mutualism between nucleus and mitochondrion, since mitochondrial endosymbiosis began about 2 billion years ago. This mostly cooperative interaction has provided the basis for eukaryotic expansion and diversification, which has profoundly altered the forms of life on Earth. While we ignore the exact biochemical details of how the alpha-proteobacterial ancestor of mitochondria entered into endosymbiosis with a proto-eukaryote, in more general terms, we present a signaling games perspective of how the cooperative relationship became established, and has been maintained. While games are used to understand organismal evolution, information-asymmetric games at the molecular level promise novel insights into endosymbiosis. Using a previously devised biomolecular signaling games approach, we model a sender–receiver information asymmetric game, in which the informed mitochondrial sender signals and the uninformed nuclear receiver may take actions (involving for example apoptosis, senescence, regeneration and autophagy/mitophagy). The simulation shows that cellularization is a stabilizing mechanism for Pareto efficient sender/receiver strategic interaction. In stark contrast, the extracellular environment struggles to maintain efficient outcomes, as senders are indifferent to the effects of their signals upon the receiver. Our hypothesis has translational implications, such as in cellular therapy, as mitochondrial medicine matures. It also inspires speculative conjectures about how an analogous human–AI endosymbiosis may be engineered.