Abstracts
Cryo-EM reveals the compositional landscape of the mammalian mitochondrial respiratory supercomplexes
Irene Vercellino
Forschungszentrum Jülich GmbH, Ernst Ruska Centre For Microscopy and Spectroscopy with Electrons, Wilhelm-Johnen-Straße , 52428 Jülich [DE], i.vercellino@fz-juelich.de
Author(s):
Irene Vercellino, Leonid Sazanov
The mitochondrial respiratory chain (MRC) is central to mammalian metabolism. The MRC complexes are functional in isolation but associate in the membrane in high-order structures named supercomplexes. Important open questions regarding the assembly and composition of supercomplexes need to be addressed to elucidate the physiological role of supercomplexes in metabolism. Our cryo-EM work tackled the role that the supercomplex associated factor SCAF1 plays in supercomplexes assembly using murine mitochondria as mammalian model. SCAF1 is required for the assembly of supercomplex CIII2CIV, while its role in the formation of respirasome (supercomplex CICIII2CIV), featuring CIII2CIV alongside CI, is unclear. SCAF1 expression has been linked to differential fitness in humans and mice and to cancer, making it a relevant target for human health. Our structures showed that SCAF1 N-terminus inserts into CIII2, while the C-terminus binds CIV, keeping CIII2 and CIV together during the CIII2CIV assembly and in the mature form and biochemical assays proved that CIII2 and CIV gain catalytic advantage when assembled in the supercomplex. We also confirmed that SCAF1 is not present in the canonical respirasome, but we found it bound to a newly identified respirasome, explaining why SCAF1 is biochemically detected in respirasome-like species. Thus, our structures reveal the SCAF1-driven compositional landscape of mammalian supercomplexes and suggest how they can fine-tune mammalian metabolism.