Spiegelhalter, C. | Search bioRxiv

bioRxiv2023

Senescent cells deposit intracellular contents through adhesion-dependent fragmentation

Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here we identify that senescent cells dispose of large fragments of themselves through cell-to-cell adhesion, which we term senescent-cell adhesion fragments (SCAFs). Found across all senescent types examined, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreased SCAF formation but induced senescent-cell death, which was caused by an inability to shed damaged mitochondria. Dynamic analyses show that SCAFs ultimately rupture, releasing a complex proteome including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Altogether, these findings identify a new feature that facilitates senescent cell survival, but the consequence of which is external deposition of damaged intracellular contents, with implications for cancer and aging.

cell biology↗

bioRxiv2019

Functional analyses of STIM1 mutations reveal a common pathomechanism for tubular aggregate myopathy and Stormorken syndrome

Tubular aggregate myopathy (TAM) is a progressive disorder essentially involving muscle weakness, cramps, and myalgia. TAM clinically overlaps with Stormorken syndrome (STRMK), associating TAM with miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia. TAM and Stormorken syndrome arise from gain-of-function mutations in STIM1 or ORAI1, both encoding key regulators of Ca2+ homeostasis, and mutations in either gene results in excessive Ca2+ entry. The pathomechanistic similarities and differences of TAM and Stormorken syndrome are only partially understood. Here we provide functional in cellulo experiments demonstrating that STIM1 harboring the TAM D84G or the STRMK R304W mutation similarly cluster and exert a dominant effect on the wild-type protein. Both mutants recruit ORAI1 to the clusters, induce major nuclear import of the Ca2+-dependent transcription factor NFAT, and trigger the formation of circular membrane stacks. In conclusion, the analyzed TAM and STRMK mutations have a comparable impact on STIM1 protein function and downstream effects of excessive Ca2+ entry, highlighting that TAM and Stormorken syndrome involve a common pathomechanism.

molecular biology↗