Mic10 Oligomerizes to Bend Mitochondrial Inner Membranes at Cristae Junctions

Abstract

The mitochondrial inner membrane is highly folded and displays a complex molecular architecture. Cristae junctions are highly curved tubular openings that separate cristae membrane invaginations from the surrounding boundary membrane. Despite their central role in many vital cellular processes like apoptosis, the details of cristae junction formation remain elusive. Here we identify Mic10, a core subunit of the recently discovered MICOS complex, as an inner mitochondrial membrane protein with the ability to change membrane morphology in vitro and in vivo. We show that Mic10 spans the inner membrane in a hairpin topology and that its ability to sculpt membranes depends on oligomerization through a glycine-rich motif. Oligomerization mutants fail to induce curvature in model membranes, and when expressed in yeast, mitochondria display an altered inner membrane architecture characterized by drastically decreased numbers of cristae junctions. Thus, we demonstrate that membrane sculpting by Mic10 is essential for cristae junction formation.

An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

“…Interestingly, the MICOS subunit Mic10 was found to be strongly enriched at the sites where septa membranes meet the IBM and the bending of septa is strongest (Figure 5E). This observation is in line with the finding that this MICOS subunit has an important role in the formation of the narrow ring or slot like structure of the crista junctions (Barbot et al, 2015; Bohnert et al, 2015; Milenkovic and Larsson, 2015). …”

“…Assembly of CJs can take place since a pool of MICOS subunits is present in the IBM (Harner et al, 2011). Interestingly, oligomeric forms of the MICOS subunit Mic10 can induce membrane curvature in vitro and were suggested to form CJs in vivo (Barbot et al, 2015; Bohnert et al, 2015; Milenkovic and Larsson, 2015). We propose that the shape of CJs formed by the MICOS complex determines the tubular shape of nascent cristae.…”

Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control

“…Mic19 connects the two sub-complexes (Friedman et al., 2015). This picture is less clear in mammals: first, a homolog of Mic12 has not been yet identified; second, the existence of these two sub-complexes remains unexplored (Huynen et al., 2016); third, silencing of the mammalian homolog of yeast Mic10 does not alter cristae shape, whereas in yeast, its deletion results in a thylakoid-like cristae morphology (Alkhaja et al., 2012, Barbot et al., 2015, Bohnert et al., 2015). Thus, MICOS complex composition and regulation may have changed during vertebrate evolution, perhaps to accommodate its recruitment into the process of apoptotic cristae remodeling.…”

Regulated membrane remodeling by Mic60 controls formation of mitochondrial crista junctions

“…The Mic10 subcomplex includes the IM-integrated proteins Mic12/QIL1, Mic26 and Mic27, whereas the second subcomplex is formed by Mic60 and the peripheral IM protein Mic19 (together with the Mic19 paralogue Mic25 in mammals)3334353637. Mic10 is a small integral IM protein with two transmembrane (TM) domains that has recently been shown to oligomerize via conserved glycine motifs, leading to the deformation of membranes in vitro and in vivo 3338. Accordingly, a function of Mic10 in bending the mitochondrial IM has been proposed.…”