Mitochondrial fusion requires an alternating salt bridge between CMT2A-associated disease residues that enable GTP hydrolysis; Fzo1 ubiquitylation then licenses post-fusion recycling by Cdc48.

Mitochondrial fusion requires a conformational change in α4 of the GTPase domain, followed by AAA-ATPase regulation, thus revealing striking mechanistic similarities between small and large GTPases.

Eukaryotic cells are subdivided into membranebound compartments specialized in different cellular functions and requiring dedicated sets of proteins. Although cells developed compartmentspecific mechanisms for protein quality control, chaperones and ubiquitin are generally required for maintaining cellular proteostasis. Proteotoxic stress is signalled from one compartment into another to adjust the cellular stress response. Moreover, transport of misfolded proteins between different compartments can buffer local defects in protein quality control. Mitochondria are special organelles in that they possess an own expression, folding and proteolytic machinery, of bacterial origin, which do not have ubiquitin. Nevertheless, the importance of extensive crosstalk between mitochondria and other subcellular compartments is increasingly clear. Here, we will present local quality control mechanisms and discuss how cellular proteostasis is affected by the interplay between mitochondria and the ubiquitin proteasome system.