Details

Autor(en) / Beteiligte

• Joy, Jery
• Barrio, Lara
• Santos-Tapia, Celia
• Romão, Daniela
• Giakoumakis, Nikolaos Nikiforos
• Clemente-Ruiz, Marta
• Milán, Marco

Titel

Proteostasis failure and mitochondrial dysfunction leads to aneuploidy-induced senescence

Ist Teil von

• Developmental cell, 2021-07, Vol.56 (14), p.2043-2058.e7

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2021

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• Aneuploidy, an unbalanced number of chromosomes, is highly deleterious at the cellular level and leads to senescence, a stress-induced response characterized by permanent cell-cycle arrest and a well-defined associated secretory phenotype. Here, we use a Drosophila epithelial model to delineate the pathway that leads to the induction of senescence as a consequence of the acquisition of an aneuploid karyotype. Whereas aneuploidy induces, as a result of gene dosage imbalance, proteotoxic stress and activation of the major protein quality control mechanisms, near-saturation functioning of autophagy leads to compromised mitophagy, accumulation of dysfunctional mitochondria, and the production of radical oxygen species (ROS). We uncovered a role of c-Jun N-terminal kinase (JNK) in driving senescence as a consequence of dysfunctional mitochondria and ROS. We show that activation of the major protein quality control mechanisms and mitophagy dampens the deleterious effects of aneuploidy, and we identify a role of senescence in proteostasis and compensatory proliferation for tissue repair. [Display omitted] •Protein quality control mechanisms are near saturation in aneuploid cells•Mitochondrial dysfunction and impaired mitophagy contribute to ROS production•Autophagy or mitophagy activation dampens the deleterious effects of CIN•JNK promotes a senescent state that drives compensatory proliferation and proteostasis High levels of aneuploidy induce a state of senescence in epithelial cells. Joy et al. identify the cascade of events that lead to JNK-driven cell senescence as a consequence of the production of an aneuploid karyotype in Drosophila.