Detection of a Mitochondrial Fragmentation and Integrated Stress Response Using the Cell Painting Assay

Mitochondria are cellular powerhouses and are crucial
for cell
function. However, they are vulnerable to internal and external perturbagens
that may impair mitochondrial function and eventually lead to cell
death. In particular, small molecules may impact mitochondrial function,
and therefore, their influence on mitochondrial homeostasis is at
best assessed early on in the characterization of biologically active
small molecules and drug discovery. We demonstrate that unbiased morphological
profiling by means of the cell painting assay (CPA) can detect mitochondrial
stress coupled with the induction of an integrated stress response.
This activity is common for compounds addressing different targets,
is not shared by direct inhibitors of the electron
transport chain, and enables prediction of mitochondrial stress induction
for small molecules that are profiled using CPA.