AMBRA1-induced mitophagy: A new mechanism to cope with cancer?

Abstract

Dysfunctions in mitophagy, the process by which mitochondria are eliminated, are associated with cancer. We found that the proautophagic protein AMBRA1 (activating molecule in beclin 1 regulated autophagy) binds the autophagosome adapter LC3, and that this interaction is crucial for mitochondrial clearance with or without involvement of the E3-ligase PARKIN. The discovery of a novel mitophagy pathway has the potential to promote new anticancer strategies.

Keywords: AMBRA1; cancer; mitophagy.

Figure 1.

AMBRA1, a novel mitophagy receptor. The PINK1/PARKIN pathway is induced after mitochondrial membrane depolarization (indicated as _ΔΨm decrease in the figure). PINK1 (PTEN-induced putative kinase1) is stabilized on the mitochondria and allows mitochondrial recruitment of PARKIN. PARKIN ubiquitylates mitochondria (ubiquitin molecules are indicated as “Ub” in the figure), which can then be recognized by the cargo protein p62. AMBRA1 (activating molecule in beclin 1 regulated autophagy) plays a crucial role in triggering mitochondria degradation by interacting with LC3 through its LIR (LC3-interacting region) motif. Furthermore, high levels of AMBRA1-ActA at the mitochondria are able to induce massive mitophagy in both PARKIN-dependent and -independent context. It is likely that an E3 ubiquitin ligase is involved in mitochondria ubiquitylation following AMBRA1-ActA expression. Based on our knowledge of other mitophagy receptors, a kinase is probably involved in the post-translational regulation of AMBRA1 under mitochondrial stress. Finally, in cancer, an increase in BCL2 expression leads to inhibition of PARKIN-mediated mitophagy and, most likely, AMBRA1-mediated mitophagy.