Sam50–Mic19–Mic60 axis determines mitochondrial cristae architecture by mediating mitochondrial outer and inner membrane contact

Abstract

Mitochondrial cristae are critical for efficient oxidative phosphorylation, however, how cristae architecture is precisely organized remains largely unknown. Here, we discovered that Mic19, a core component of MICOS (mitochondrial contact site and cristae organizing system) complex, can be cleaved at N-terminal by mitochondrial protease OMA1 under certain physiological stresses. Mic19 directly interacts with mitochondrial outer-membrane protein Sam50 (the key subunit of SAM complex) and inner-membrane protein Mic60 (the key component of MICOS complex) to form Sam50-Mic19-Mic60 axis, which dominantly connects SAM and MICOS complexes to assemble MIB (mitochondrial intermembrane space bridging) supercomplex for mediating mitochondrial outer-and inner-membrane contact. OMA1-mediated Mic19 cleavage causes Sam50-Mic19-Mic60 axis disruption, which separates SAM and MICOS and leads to MIB disassembly. Disrupted Sam50-Mic19-Mic60 axis, even in the presence of SAM and MICOS complexes, causes the abnormal mitochondrial morphology, loss of mitochondrial cristae junctions, abnormal cristae distribution and reduced ATP production. Importantly, Sam50 displays punctate distribution at mitochondrial outer membrane, and acts as an anchoring point to guide the formation of mitochondrial cristae junctions. Therefore, we propose that Sam50-Mic19-Mic60 axis-mediated SAM-MICOS complexes integration determines mitochondrial cristae architecture.

Shaping the mitochondrial inner membrane in health and disease

“…In mammalian cells, MICOS and SAM form a stable supercomplex that was termed mitochondrial intermembrane space bridging complex (MIB) (Fig. ) . These interactions support the import of a subset of mitochondrial proteins, and, importantly, they establish contact sites between the two mitochondrial membranes .…”

“…By bridging the membranes, contact sites also play a role in phospholipid transfer and biosynthesis (see section on ‘Non‐bilayer‐forming phospholipids’). Moreover, multiple studies have found that downregulation of SAM decreases the number of crista junctions , suggesting that contact sites are required for crista junction stability, perhaps by acting as an anchor. Contact site formation does not depend on the entire MICOS complex, but is mediated by the MIC60 subcomplex.…”

“…The MIC60 subcomplex includes Mic19, a peripheral membrane protein that regulates Mic60 functions, and in vertebrates additionally Mic25, a homolog of Mic19 (Fig. ) . Mic19 interacts with the mitofilin domain of Mic60 via its CHCH (coiled‐coil helix coiled‐coil helix) domain, which positively regulates the membrane remodelling activity of Mic60 .…”

“…These observations may be explained by Mic19‐mediated regulation of Mic60 oligomerization. In mammals, Mic19 was suggested to participate in linking Mic60 and SAM via a Mic60–Mic19–Sam50 axis . All MICOS subunits are encoded by nuclear genes and are synthesized as precursor proteins in the cytosol.…”

“…Interestingly, the biogenesis of Mic19 additionally depends on amino‐terminal myristoylation that mediates binding of the precursor to the TOM complex . Human Mic19 was recently reported to be a target of stress‐induced proteolysis by the metalloprotease OMA1, resulting in destabilization of the MIB complex, indicating that MICOS‐mediated contact site formation may be subject to regulation .…”