The PARL family of mitochondrial rhomboid proteases

Abstract

Rhomboids are an ancient and conserved family of intramembrane-cleaving proteases, a small group of proteolytic enzymes capable of hydrolyzing a peptide bond within a transmembrane helix that anchors a substrate protein to the membrane. Mitochondrial rhomboids evolved in eukaryotes to coordinate a critical aspect of cell biology, the regulation of mitochondrial membranes dynamics. This function appears to have required the emergence of a structural feature that is unique among all other rhomboids: an additional transmembrane helix (TMH) positioned at the N-terminus of six TMHs that form the core proteolytic domain of all prokaryotic and eukaryotic rhomboids. This "1+6" structure, which is shared only among mitochondrial rhomboids, defines a subfamily of rhomboids with the prototypical family member being mammalian Parl. Here, we present the findings that in 11 years have elevated mitochondrial rhomboids as the gatekeepers of mitochondrial dynamics and apoptosis; further, we discuss the aspects of their biology that are bound to introduce new paradigm shifts in our understanding of how the organelle uses this unique type of protease to govern stress, signaling to the nucleus, and other key mitochondrial activities in health and disease.