Dr. Reymond Sutandy, Max Planck Institute Bad Nauheim

Mitochondria rely on a dedicated protein quality control network to maintain their proteome. When misfolded or aggregated proteins accumulate beyond the capacity of this network, cells activate the mitochondrial unfolded protein response (UPRmt). This transcriptional program increases the expression of genes involved in mitochondrial protein quality control, helping the organelle cope with proteotoxic stress. In human cells, we found that UPRmt activation requires two signals generated during mitochondrial proteotoxic stress: mitochondria-derived reactive oxygen species (ROS) and mitochondrial precursor proteins that accumulate in the cytosol when import is impaired. Mitochondria-derived ROS oxidize the cytosolic co-chaperone DNAJA1, which recruits HSP70 to the accumulated precursors. This draws HSP70 away from its inhibitory interaction with heat shock factor 1 (HSF1), allowing HSF1 to activate the transcriptional response. We also found that human senescent cells have a reduced capacity to activate the UPRmt through ROS signaling. This defect may contribute to phenotypes associated with cellular senescence and could offer a strategy to selectively target senescent cells in aging and age-related diseases.