Retrograde rearrangement of mitochondria correlates with nuclear deformation and genotoxic damage

Author(s): Maximilian Jobst, Francesco Crudo, Doris Marko, Andrea Bileck, Samuel Matthias Meier-Menches, Christopher Gerner, Giorgia Del Favero
Abstract: The elucidation of molecular mechanisms underlying DNA damage and repair belongs to the fundamental questions of pathophysiology and toxicology. Increasing attention is focusing on the role of mechanical stress exerted on the nucleus and its function as a mechanosensor. Hypothesizing that physical cues arising from the intracellular rearrangements could contribute to the genotoxic damage, we observed that the retrograde relocalization of the mitochondria coincides with increased nuclear stiffness in T24 bladder cells. Perinuclear mitochondrial clustering aligned with the deformation of the nucleus and was accompanied by DNA strand breaks. In the tested experimental layouts, these events appeared scarcely dependent on oxidative stress, strengthening a possible contribution of mechanical nuclear deformation. Proof of principle experiments in SK-OV-3 and HCT 116 cells underpinned the role of cellular architecture and its heterogeneity. These findings open new avenues for understanding how physical changes in the intracellular compartment may drive genotoxicity, potentially supporting genetic instability and carcinogenesis.
Organisation(s): Department of Food Chemistry and Toxicology, Core Facility Multimodal Imaging, Joint Metabolome Facility, Department of Analytical Chemistry, Department of Inorganic Chemistry
External organisation(s): Vienna Doctoral School in Chemistry (DoSChem)
Journal: Iscience
Volume: 28
ISSN: 2589-0042
DOI: https://doi.org/10.1016/j.isci.2025.112955
Publication date: 08-2025
Peer reviewed: Yes
Austrian Fields of Science 2012: 104004 Chemical biology, 301211 Toxicology
Keywords
ASJC Scopus subject areas: General
Portal url: https://ucrisportal.univie.ac.at/en/publications/da52149f-f2f8-44b4-b17d-631e7bd67eef