Exploring the activation mechanism of the Mic60 subcomplex governing mitochondrial crista junctions
Year: 2026
Type: preprint
Abstract: Crista junctions (CJs) are narrow infoldings of the inner mitochondrial membrane, serving as entry points into the cristae microenvironment. The mitochondrial contact site and cristae organizing system (MICOS) complex is a highly conserved protein machinery controlling CJ biogenesis and architecture, but its assembly mechanism driving CJ formation has remained unclear. By determining a crystal structure of a Chaetomium thermophilum Mic60-Mic19 complex and combining it with modelling and mutagenesis studies, we identify an extended helical region (EHR) of the Mic60 mitofilin domain and a further Mic19 helix as crucial elements of complex formation. In vitro cross-linking data and hydrogen-deuterium exchange mass spectrometry resolve domain assembly and conformational dynamics of the Mic60-Mic19 subcomplex and point to the EHR as a molecular switch controlling Mic60 transition from a closed dimer to a Mic19-bound hetero-octamer. Our data provide a structural model for Mic60 activation and therefore MICOS assembly as a prerequisite for crista junction formation.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Deutsche Forschungsgemeinschaft
Awards: G2146881008, G3134524351
OpenAlex ID: W7220452673