Mitochondrial Cristae Architecture and Functions: Lessons from Minimal Model Systems

Abstract

Mitochondria are known as the powerhouse of eukaryotic cells. Energy production occurs in specific dynamic membrane invaginations in the inner mitochondrial membrane called cristae. Although the integrity of these structures is recognized as a key point for proper mitochondrial function, less is known about the mechanisms at the origin of their plasticity and organization, and how they can influence mitochondria function. Here, we review the studies which question the role of lipid membrane composition based mainly on minimal model systems.

Keywords: cardiolipin; cone-shaped lipid asymmetry; cristae; curvature-based sorting; mitochondria; nonbilayer structures.

Figure 1

Structure of mitochondrial microcompartments. (A) Schematic representation of mitochondrial architecture. The outer mitochondrial membrane (OMM), inner mitochondrial membrane (IMM), inner boundary membrane (IBM), cristae junctions (CJ), intermembrane space (IMS), cristae membrane (CM) and mitochondrial matrix are indicated. (B) Electron micrograph from a cryo cut mitochondrion with antibody probing of OXPHOS complexes. The localization in the cristae membrane is obvious. Inset: detailed view of the two IMM compartments CM and IBM connected by the cristae junction (CJ). Scale bar: 150 nm. Reproduced with permission from Frey et al. [15], Trends Biochem. Sci.; published by Elsevier, 2000.

Figure 2

Mitochondrial model with a single cristae. (A) Proton concentration distribution (expressed as pH) in the inner mitochondrial space (cristae and non-cristae portions). (B) Geometry used to investigate the effect of detailed cristae morphology. (C) Effect of the surface-to-volume ratio (SVR) on the average PMF on the cristae membrane ($\mathsf{\Delta }{p}_{CM}$). Reproduced with permission from Song et al. [34], Phys. Rev. E; published by the APS, 2013.

Figure 3

Illustration of the cross section of a mitochondrion observed under different metabolic conditions. The condensed morphology appears in the presence of high ADP concentrations, when mitochondria are producing ATP (state III), while the orthodox configuration occurs at low ADP concentrations, with no production of ATP (state IV). Reproduced with permission from Manella [25], Biochim. Biophys. Acta; published by Elsevier, 2006.

Figure 4

Molecular geometry of lipids and membrane stored stress. Monolayers made of cylindrical molecules of zero spontaneous curvature (SC) can form nonstressed lamellas (first column, green lipid). However, for nonzero SC, lipid molecules have to be reshaped to fit into a flat state, leading to membrane stress (second column, orange lipid). When the stress accumulated in the resulting bilayer is too big, the transition of the lamella into a nonlamellar phase is favorable. The transition begins when small interlamellar contacts having characteristic hourglass shape form (third column, red lipid), lipids with negative SC promotes formation of these localized nonbilayer structures [12].

Figure 5

Curvature frustration illustrated for the case of a symmetric bilayer consisting of two monolayers that have an inherent desire to bend. In order to avoid energetically unfavourable voids (blue triangles), the two monolayers must lie flat back-to-back, resulting in a stored curvature elastic stress [10].

Figure 6

Cristae-like membrane invaginations. (A) Modulation of local pH gradient at membrane level of a cardiolipin containing vesicle induces dynamic cristae-like membrane invaginations. GUV is made of PC/PE/CL 60:30:10 mol/mol in buffer at pH 8. The local delivery of HCl (100 mM pH 1.6), which lowers the local pH, is carried out by a micropipette (its position is pointed by the arrow in frame t = 0 s).The induced membrane invagination (frame 22.8 s) is completely reversible (frames 38.7–66.4) as far as the acid delivery is stopped. Geometrical features of the tubular invagination calculated from the model as a function of the area reduction factor $\lambda$ that is controlled by the acid delivery (the lower $\lambda$, the stronger acid effect): (B) Radius of the tube normalized by the radius of the initial vesicle. (C) Aspect ratio of the tube. Both are given for three experimentally relevant values of the reduced volume v of the initial vesicle. Two experimental illustrations are given for $\nu$ = 0.85 and 0.75 and L/(2r) ratios ∼40 and 14, respectively. Reproduced with permission from Khalifat et al. [86], Biophys. J.; published by Elsevier, 2008.

Figure 7

Mitochondrial cristae modeled as an out-of-equilibrium membrane driven by a proton field. Schematic representation of a cristae: (A) The plots represent the proton concentration on the surface in states III and IV. The tubes represent the shape of the invagination in state III and IV; (B) Deformation fields of the membrane and intrinsic basis of the deformed surface. (C) Changes in the cylindrical shaped model cristae morphology as the mitochondrion transitions between the two mitochondrial states IV and III. Reproduced with permission from Patil et al. [94], Phys. Rev. E; published by the APS, 2020.

Figure 8

(Left) Images and intensity profiles of tubes pulled from GUVs containing CL for large (R ≈ 37 nm) and small (R ≈ 10 nm) tube radii. (Middle) Box plots comparing the sorting ratio for curved tubes pulled from GUVs containing green fluorescent lipids. CL is enriched in the tubes comparing with the lipid control. (Right) CL enrichment as a function of CL density in GUVs for four ranges of tube curvature. Dashed and solid lines represent respectively the minimum square fit to the non-interacting and interacting uncoupled model (no or possible CL-CL interactions). Reproduced with permission from Beltrán-Heredia et al. [80], Commun. Biol.; published by Nature Publishing Group, 2019.

Figure 9

CL asymmetric distribution between the inner and outer leaflet of a LUV. The LUV have a diameter of 100 nm and are made of CL/PC with different CL concentrations. Reproduced with permission from Elmer-Dixon et al. [125], J. Phys. Chem. B; published by the ACS, 2019.

Figure 10

Giant vesicles as model systems. (A) Confocal image of a GUV made of EPC/CL 60:40 mol% showing the distribution of Top-Fluor CL (green channel) and Bodipy-TR Ceramide (red channel), 22 ${}^{\circ }$C, scale bar is 5 µm, [80]. (B) Confocal microscopy of GUVs made of PC/CL 90:10 and 80:20 mol%, room temperature, scale bar is 50 µM, [139]. (C) GUVs made of composed of (18:0–22:6)PC/(16:0–20:4)PE/(18:2)${}_4$CL/DOPI/DOPS/Chol (39.9:30:20:5:3:2 mol% and giant mitochondrial vesicles (GMVs) from native phospholipids extracted visualized by Texas Red DHPE (left) and by NAO (right) at 0.1 mol%. room temperature, scale bars are 10 µm, [100]. (D) Laurdan GP image of isolated EPC/EPE/CL (50:25:25) mol% membrane, room temperature, scale bar is 5 µm, [141]. (E) Fluorescence and optic microscopy images of POPC/DOPE/CL (49:30:20) GUV containing 0.5 mol% TopFluor-CL, 25 ${}^{\circ }$C, [140]. (F) Phase contrast images of GUVs made of POPC/CL (70:30) mol%, 23 ${}^{\circ }$C, [142]. Reproduced with permissions from respectively Beltrán-Heredia et al., Pennington et al., Jalmar et al., Kawai et al., Cheniour et al., and Tomšié et al. [80,100,139,140,141,142], in respectively Commun. Biol., J. Biol. Chem., Cell Death Dis., J. Phys. Chem. B, Biochim. Biophys. Acta, and J. Chem. Inf. Model; published respectively by Nature Publishing Group (2019), Elsevier (2018), Nature Publishing Group (2010), ACS (2014), Elsevier (2017), and ACS (2005).

Figure 11

Relative quantitative distribution of different lipid phases as function temperature of POPC/POPE (0.5:0.5), POPC/CLmix (0.7:0.3), POPE/CLmix (0.6:0.4) and POPC/POPE/CLmix (0.5:0.3:0.2) in the studied temperature range. pH 7.4, 0.1 mM NaCl. Reproduced with permission from Lopes et al. [144], Biochim. Biophys. Acta; published by Elsevier, 2017.

Figure 12

A proposed model of the molecular mechanism underlying the mitochondrial uncoupling in HACD1-deficient muscles. In wild type conditions, anionic lipids included in the cristae lumen leaflet of the IMM contribute to the translocation of protons to the tip of the cristae, where ATP synthase oligomers concentrate. In Hacd1-KO mice, the decreased content of anionic lipids changes cristae shape, reduces efficiency of proton translocation, hence impairing ATP production.

Figure 13

Illustration of Gasanov et al’s hypothesis suggesting the inverted micellar organization of cristae membranes (shown by red brackets). Reproduced with permission from Gasanov et al. [102], Biochim. Biophys. Acta.; published by Elsevier, 2018.