Shared Structural Features of Miro Binding Control Mitochondrial Homeostasis

Abstract

Miro proteins are universally conserved mitochondrial calcium-binding GTPases that regulate a multitude of mitochondrial processes, including transport, clearance and lipid trafficking. Miro binds a variety of client proteins involved in these functions. How this binding is operated at the molecular level and whether and how it is important for mitochondrial health, however, remains unknown. Here, we show that known Miro clients all use a similar short motif to bind the same structural element: a highly conserved hydrophobic pocket in the calcium-binding domain of Miro. Using these Miro-binding motifs, we identified direct interactors de novo, including yeast Mdm34, and mammalian MTFR1/2/1L, VPS13D and Parkin. Given the shared binding mechanism and conservation across eukaryotes, we propose that Miro is a universal mitochondrial adaptor coordinating mitochondrial health. One-Sentence SummaryFunctionally diverse mitochondrial proteins interact with a conserved hydrophobic pocket on the calcium-binding Miro-GTPases.