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Title: Proteostasis failure and mitochondrial dysfunction leads to aneuploidy-induced senescence
Author: Joy, Jery
Barrio, Lara
Santos Tapia, Celia
Romão, Daniela
Giakoumakis, Nikolaos Nikiforos
Clemente Ruiz, Marta
Milán, Marco
Keywords: Drosòfila
Issue Date: 2-Jul-2021
Abstract: 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.
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It is part of: Developmental Cell, 2021, vol. 56, num. 14, p. 2043-2058.e7
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ISSN: 1534-5807
Appears in Collections:Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

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