Why do mitochondria look like they do?

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One of the biggest challenges in biology today is explaining the structure of cristae, the inner membranes of mitochondria. The explanation in this case is a set of principles for predicting the shape the crystals will take after basic metabolic manipulation of the environment in which the mitochondria are located. Thus, these principles would be a description of the true function of mitochondria, something that has hitherto only hardly imagined.

Recent advances in techniques such as super-resolution live-cell microscopy and electron tomography have given new insight into the dynamic behavior of craters. A detailed structure of the entire mitochondrial volume can now be generated from a series of tilt images that are projected back to create 3D cross-sectional images. On Monday, we discussed how cristae form and remodel according to the abundance and health of several endomembrane and matrix proteins. The pretext for this analysis was the structural and biochemical similarities between membranes in mitochondria, thylakoids, and myelin that supposedly help direct metabolites in energy production.

In a recent article from the Royal Society open biology, the authors explain cristae biogenesis through the coordinated activities of four major evolutionarily conserved pathways from protists and yeasts to higher eukaryotes like us: 2D formation and lack of ATP complex formation at the cristae edges, mitochondrial connection site assembly and the cristae organization system (MICOS) at crista junctions, membrane remodeling by inner membrane-associated GTPase (Mgm1 in yeast and OPA1 in mammals) and appropriate adaptation of membrane lipogenesis.

For the first pathway involving ATP synthase, several things emerge. As mentioned earlier, the spontaneous reduction of the ATP-synthase complex at precisely defined and species-dependent angles in ordered rows dictates the geometry of the ground floor. In contrast to respiratory complexes I-IV, which are assembled on the flat inner boundary membrane, ATP-synthase (compound V) is fully assembled deep within cristae membranes. While many ATP-synthase subunit proteins are dispensable for proper cristae formation, Atp20 and Atp21 subunits are strictly required.

An excess of ADP results in an intense morphology with large bulging spaces within the crystal. In contrast, under conditions of ADP restriction, mitochondria adopt an orthogonal morphology with a contracting intra-crystal space. In the giant amoeba Chaos carolinensis, mitochondria usually contain randomly oriented tubular cristi. With starvation, the enlarged carrists adopt a cuboid shape with a zigzag pattern. In mice, apoptotic factors cause the fusion of individual crystals with subsequent release of cytochrome c from the intracrystalline space into the border region.

لماذا تبدو الميتوكوندريا كما تبدو؟ open biology (2021). doi: 10.1098/rsob.210238”/>

credit: Klicker & Westerman, open biology (2021). doi: 10.1098/rsob.210238

For the second pathway, the assembly of MICOS contact sites, the research identified critical proteins such as those in the MIC60-related gene family found in the ancestors of mitochondrial endosymbiosis – α-proteobacteria. Many early mitochondrial ancestors show divergent intracytoplasmic membrane structures. Invariably, species that have simplified their mitochondria so much that cristae are absent correspondingly lack MICOS-related genes. Re-expression of MIC60 homologues in yeast Δmic60 mutants rescues ultrastructural mitochondrial defects.

The third pathway includes dynamin-related GTPases, which coordinate fusion and fission of both the inner and outer membranes. In fission, these proteins cleave into contractile loops that apply restraining forces to compressive mitochondria. It is now understood that the outcome depends on the interactions of these proteins, with both the MICOS complex and cristae junctions, as well as the inner and outer membrane transport systems that assemble there. These include the TIM and TOM transmembrane translation complexes.

The fourth pathway involves the mitochondrial membrane phospholipids themselves. Mitochondria contain the cardiolipin biosynthesis pathway, and are also involved in the synthesis of phosphatidylethanolamine. Along with phosphatidylcholine, these are the three main phospholipids that mitochondria work with. Most of the building blocks of mitochondrial lipids are synthesized in the ER, and therefore must be imported through mechanisms involving close proximity to the ER. Once inside the outer membrane, lipid distribution is mediated by transmembrane- and space-localized transport proteins of the Ups/PRELI family,

Mitochondria do not create engineering from scratch, but rather harness and build on the natural physical forms that occur spontaneously in lipids. The lipids are left to their own devices, and form concentric lamellar structures that can then be expanded and augmented by specific proteins. Careful measurements have now revealed that individual crystals are functionally independent and can have significantly different membrane potentials.

Cristae formation comprises a closely related interaction of the above four formation effects. For example, the activities of the MICOS complex and the dimerization of ATP synthase are cooperative and antagonistic. MICOS causes negative membrane curvature while ATP synthase causes positive curvature at the tips and edges of the cristae. New computational models, as they are currently under development in laboratories around the world, in which the proportions of these various components can be finely tuned and tweaked, will greatly help in determining what controls the shape of mitochondria.

Unexpected insights into the dynamic structure of mitochondria

more information:
Til-Clicker et al., Pathways that make up the inner mitochondrial membrane, open biology (2021). doi: 10.1098/rsob.210238

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