Fig. 4.

Mito-nuclear contacts as catalysts of the mitochondrial retrograde response. Dysfunctional mitochondria that escape the quality control by mitophagy enlarge the size of the mitochondrial network, increasing proximity with the nuclear envelope. Such a gain in space establishes contacts between dysfunctional mitochondria (represented by dashed OMM) and the nucleus to facilitate MRR and hence sustain pathogenic signalling. The outer mitochondrial membrane protein TSPO is required for the formation of the nucleus–mitochondria tethering complex together with ABCD3, PKA and AKAP95. Notably, TSPO when accumulated on the mitochondria prevents Parkin-mediated mitophagy thus emerging as a valuable tool to inform the link between declined mitophagy and increased MRR