Abstract
Impaired mitochondrial function and accumulation of DNA damage have been recognized as hallmarks of age-related diseases. Mitochondrial dysfunction initiates protective signalling mechanisms coordinated at nuclear level particularly by modulating transcription of stress signalling factors. In turn, cellular response to DNA lesions comprises a series of interconnected complex protective pathways, which require the energetic and metabolic support of the mitochondria. These are involved in intracellular as well as in extracellular signalling of damage. Here, we have initiated a study that addresses how mitochondria-nucleus communication may occur in conditions of combined mitochondrial dysfunction and genotoxic stress and what are the consequences of this interaction on the cell system. In this work, we used cells deficient for PINK1, a mitochondrial kinase involved in mitochondrial quality control whose loss of function leads to the accumulation of dysfunctional mitochondria, challenged with inducers of DNA damage, namely, ionizing radiation and the radiomimetic bleomycin. Combined stress at the level of mitochondria and the nucleus impairs both mitochondrial and nuclear functions. Our findings revealed exacerbated sensibility to genotoxic stress in PINK1-deficient cells. The same cells showed an impaired induction of bystander phenomena following stress insults. However, these cells responded adaptively when a challenge dose was applied subsequently to a low-dose treatment to the cells. The data demonstrates that PINK1 modulates intracellular and intercellular signalling pathways, particularly adaptive responses and transmission of bystander signalling, two facets of the cell-protective mechanisms against detrimental agents.
Highlights
Mitochondria have crucial functions in the cell, including ATP generation, iron-sulfur cluster biogenesis, nucleotide biosynthesis, metabolism, calcium homeostasis, and cell death regulation
The choice of the genotoxic treatments was made considering that throughout lifetime, the human body is exposed to DNA damage factors at low levels through environmental exposures and at higher levels in the context of medical exposures for diagnostic and/or treatment [39]
Besides the measures of DNA damage accumulation, we have investigated the behaviors of other cellular parameters following genotoxic stress to address the role of mitochondria modulated by PINK1 in the maintenance of cellular homeostasis in response to DNA damage induced by BLM
Summary
Mitochondria have crucial functions in the cell, including ATP generation, iron-sulfur cluster biogenesis, nucleotide biosynthesis, metabolism, calcium homeostasis, and cell death regulation. As mitochondrial biogenesis is controlled by the nucleus and most mitochondrial proteins are encoded by nuclear genes, a tight communication network between mitochondria and the nucleus has evolved, comprising signalling cascades, proteins with dual localization to the two compartments, and sensing of mitochondrial products by nuclear proteins [1]. These enable an organellar crosstalk that facilitates integration of cellular and environmental signals to adjust their function for the maintenance of cellular homeostasis at functional checkpoints in the cellular life
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