Organelle interdependencies underly the collapse of eukaryotic intracellular organization during cell death and aging

Athanasios Litsios^1,2†*, Dara Lo^1,3†, Arthur Fischbach^4†, Helena Friesen¹, Alex Daiejavad^1,3, Nil Sahin^1,3, Myra Paz David Masinas¹, Thuy Nguyen1^1,3, Carles Pons^7,8, Jing Hou¹, Quaid Morris^1,3,5, Thomas Nyström^4*, Charles Boone^1,3,6*, Brenda J. Andrews^1,3*Ŧ

• ¹Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada
• ²Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra (UPF), Barcelona, Spain
• ³Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
• ⁴4Department of Medical Biochemistry and Cell Biology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden. Medicinaregatan 9A-C, 413 90
• ⁵Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
• ⁶RIKEN Center for Sustainable Resource Science, Wako, 351-0198 Saitama, Japan
• ⁷Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology (BIST), 08028 Barcelona, Catalonia, Spain
• ⁸Department of Biomedicine, Faculty of Medicine and Health Sciences - campus Clinic, University of Barcelona, 08036 Barcelona, Catalonia, Spain


• † These authors contributed equally to this work
• * Corresponding authors
• Ŧ Lead contact


• ^* Correspondence: brenda.andrews@utoronto.ca, charlie.boone@utoronto.ca, thomas.nystrom@cmb.gu.se, athanasios.litsios@upf.edu

Summary

Complex intracellular organization is a defining feature of eukaryotic cells, and the loss of its integrity is a hallmark of aging and disease. We combined high-content time-lapse imaging and machine learning to quantitatively monitor the morphology of 21 subcellular structures in ~70 million live yeast cells, following conditional inhibition of essential genes. We show that perturbation of essential bioprocesses impacts cellular organization in a bioprocess-specific manner, with inhibition of vesicle trafficking causing acute and systemic collapse of subcellular architecture. Local defects in intracellular organization are propagated by cascade effects, most commonly among functionally related structures, which results in the exponential collapse of intracellular organization upon breaches in its integrity. By mapping morphological defects to their impact on higher-order cellular phenotypes, we identify a threshold-dose-response relationship between the loss of intracellular organization and the onset of cell death. We also show that systemic defects in intracellular organization underly morphological changes associated with natural aging.