The model of mitochondria-nucleus communication in the maintenance of cellular homeostasis during combined mitochondrial and genotoxic stress. Mitochondria and the nucleus communicate to maintain cellular homeostasis. Mitochondria produce ATP and metabolites required for nuclear activity, while the nucleus is responsible for encoding most mitochondrial proteins (a). Following mitochondrial stress, mitochondria accumulate damage that leads to increased ROS and altered ATP production. These trigger the signalling to the nucleus that is resulting in a retrograde response consisting of transcriptional and metabolic responses designed to reestablish the cellular homeostasis (b). Genotoxic damage impacts the mitochondria primarily affecting mitochondrial protein synthesis and ATP production and enhancing oxidative stress (c). Combined stresses at the level of mitochondria and the nucleus likely to appear in aging and age-related disease impair both mitochondrial processes (e.g., mtQC) and nucleus function (e.g., DNA repair). Here, we provide examples of how cumulative genotoxic stress (DNA damage) and mitochondrial dysfunction (PINK1 loss of function) are contributing to changes in cellular homeostasis and intercellular communication (d).