EMBO J. https://doi.org/10.15252/embj.201798786 (2018)
Proteosomal inhibition results in the accumulation of protein aggregates that can promote proteotoxic effects if not removed properly. However, the redundant pathways for removing these aggregates remain unclear. While studying the cross-talk between mitochondria and the ubiquitin–proteasome system, Li et al. identified an interaction between the mitochondrial outer-membrane protein FUNDC1, which is normally involved in mitochondrial degradation, and the cytosolic chaperone protein HSC70. This interaction enables recruitment of unfolded cytosolic proteins to the mitochondria to be degraded by the mitochondrial protease LONP1 upon proteosomal inhibition. Interestingly, the actions of FUNDC1 were associated with the formation of mitochondrion-association protein aggregates (MAPAs). Loss of FUNDC1 prevented the autophagic degradation of MAPAs. Further studies showed that accumulation of proteasomal clients in mitochondria resulted in mitochondria dysfunction and cellular senescence. Though the mechanism of MAPAs formation remains unclear, these findings reveal the role of mitochondrial quality control as a backup system to properly handle cytosolic proteins under loss of proteasomal activity.