Common Traits Spark the Mitophagy/Xenophagy Interplay

Abstract

Selective autophagy contributes to the wellbeing of eukaryotic cells by recycling cellular components, disposing damaged organelles, and removing pathogens, amongst others. Both the quality control process of selective mitochondrial autophagy (Mitophagy) and the defensive process of intracellular pathogen-engulfment (Xenophagy) are facilitated via protein assemblies which have shared molecules, a prime example being the Tank-Binding Kinase 1 (TBK1). TBK1 plays a central role in the immunity response driven by Xenophagy and was recently shown to be an amplifying mechanism in Mitophagy, bring to attention the potential cross talk between the two processes. Here we draw parallels between Xenophagy and Mitophagy, speculating on the inhibitory mechanisms of specific proteins (e.g., the 18 kDa protein TSPO), how the preferential sequestering toward one of the two pathways may undermine the other, and in this way impair cellular response to pathogens and cellular immunity. We believe that an in depth understanding of the commonalities may present an opportunity to design novel therapeutic strategies targeted at both the autonomous and non-autonomous processes of selective autophagy.

Keywords: TBK1; TSPO; bacteria; mitochondria; mitophagy; xenophagy.

FIGURE 1

Tank-binding kinase 1 (TBK1) as a common functional element between Xenophagy and Mitophagy. Panel (A) depicts pivotal steps in the two processes of selective autophagy against pathogens and mitochondria in which TBK1 plays an equally important role. Panel (B) highlights instead that the similarity may embrace also inhibitory mechanisms among which the TSPO pathway is proposed (C).

FIGURE 2

Sequence alignment of mycobacterial TspOs with the human homolog. Sequences were aligned using Clustal Omega and show approximately 30% amino acid identity with the human homolog. Stars indicate identical amino acid residues and dots indicate semi-conserved (similar residues) in all three sequences.

FIGURE 3

Undermining mitochondria to establish bacterial infections. The figure depicts the ability of certain bacterial species to release mitochondria impairing toxins (i.e., antimycin to impair mitochondria) which upregulate mitophagy, perhaps as a way to hijack the common molecules used in both autophagy processes and as such allow the bacteria to propagate within the host cell.