Fig. 8.

AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome. This event is crucial and required for AMBRA1-induced mitophagy. In a second step, in analogy with other mitophagy receptors, AMBRA1 is phosphorylated at S1014, flanking its LIR motif, in order to be able to interact with mATG8s. The final outcome is the engulfment of damaged mitochondria (dark blue) into autophagosomes. This post-translational modification is controlled by IKKα kinase upon mitophagy stimulation. Reproduced from ref.⁷¹ with permission from Elsevier