Emerging Roles of the MICOS Complex in Cristae Dynamics and Biogenesis

Abstract

Mitochondria are double membrane-enclosed organelles performing important cellular and metabolic functions such as ATP generation, heme biogenesis, apoptosis, ROS production and calcium buffering. The mitochondrial inner membrane (IM) is folded into cristae membranes (CMs) of variable shapes using molecular players including the 'mitochondrial contact site and cristae organizing system' (MICOS) complex, the dynamin-like GTPase OPA1, the F₁F_O ATP synthase and cardiolipin. Aberrant cristae structures are associated with different disorders such as diabetes, neurodegeneration, cancer and hepato-encephalopathy. In this review, we provide an updated view on cristae biogenesis by focusing on novel roles of the MICOS complex in cristae dynamics and shaping of cristae. For over seven decades, cristae were considered as static structures. It was recently shown that cristae constantly undergo rapid dynamic remodeling events. Several studies have re-oriented our perception on the dynamic internal ambience of mitochondrial compartments. In addition, we discuss the recent literature which sheds light on the still poorly understood aspect of cristae biogenesis, focusing on the role of MICOS and its subunits. Overall, we provide an integrated and updated view on the relation between the biogenesis of cristae and the novel aspect of cristae dynamics.

Keywords: MICOS; cristae; cristae biogenesis; cristae dynamics; mitochondria.

Figure 1

Key regulators of mitochondrial cristae organization. The scheme shows the organization of mitochondrial membranes where the cristae are formed by invagination of the inner membrane towards the matrix. The MICOS (mitochondrial contact site and cristae organizing system) complex resides at the crista junctions (CJs) and is composed of seven subunits, MIC10, MIC13, MIC19, MIC25, MIC26, MIC27 and MIC60 (only the numbers are depicted in the figure for the ease of legibility). MICOS is required to stabilize the CJs and form the contacts between the inner and outer membranes via interaction with the SAM (sorting and assembly machinery) complex. This interaction between MICOS and the SAM complex forms the larger complex called the mitochondrial intermembrane space bridging complex (MIB) that encompasses the intermembrane space. OPA1 is also enriched at the CJs, and interaction between membrane-bound long (L-) forms and soluble short (S-) forms is required to maintain the width of the CJs. F₁F_O ATP synthase plays an important role in the formation of positive membrane curvature at the tip/rim of cristae. The OXPHOS (oxidative phosphorylation) machinery resides in the cristae membrane.

Figure 2

The MICOS complex regulates apparent cristae fusion and fission cycles. (a) Scheme depicts the various kinds of crista and CJ dynamics that are found in a mammalian cell. CJs formed by the MICOS complex move towards and away from each other in order to undergo merging and splitting events, respectively, as shown by cyan arrows. Similarly, cristae show a dynamic movement that involves continuous fusion and fission cycles in a balanced and reversible manner. In various instances, merging CJs can bring with them the adjoining cristae and facilitate their fusion along their length, resulting in the formation of a cristae network that resembles the ‘X’ or ‘Y’ letter. Cristae fusion is immediately followed by fission or vice versa. Cristae can also detach from the inner boundary membrane (IBM) to form cristae vesicles (shown as green cristae). These cristae vesicles can re-fuse to the IBM. OM represents outer membrane. (b) In MIC13 KO, cristae are arranged as concentric rings or internal stacks that are not connected to the IBM. The movement of CJs and cristae is drastically reduced in MIC13 KO cells.

Figure 3

Various roles of the MICOS complex in regulating cristae biogenesis. (a) MIC10 and MIC60 can generate membrane curvature by bending the lipid bilayer. Mic10 has a hairpin topology and the oligomerization of Mic10 results in membrane bending. Mic60 contains an amphipathic helix that is known to generate membrane curvature important for membrane bending activity. (b) The MICOS complex is shown to initiate the formation of tubular cristae in yeast that involves the influx of lipids and proteins as the primary steps. F₁F_O ATP synthase oligomers at cristae tips/rims are also depicted. (c) The lamellar cristae in yeast are proposed to be formed during the process of inner membrane fusion by Mgm-1 (OPA1 homolog). MICOS is required to complete the formation of these lamellar cristae by formation of CJs involving the assembly of the MICOS complex. (d) Mammalian MIC10 KO cells contain few tube-like cristae, and the following re-synthesis of MIC10 over time leads to a recovery of lamellar cristae. This is proposed to mainly occur via restructuring of existing unstructured tubes to form lamellar cristae rather than de novo cristae biogenesis.