19.10: The Supercomplexes in the Crista Membrane

The mitochondrial cristae membrane is the primary site for the oxidative phosphorylation (OXPHOS) process of energy conversion mediated through respiratory complexes I to V. These complexes have been widely studied for decades, and it has been proven that they form supramolecular structures called respiratory supercomplexes (SC). These higher-order complexes may be crucial in maintaining the biochemical structure and improving the physiological activity of the individual complexes while boosting the electron transfer efficiency.

Types of respiratory chain supercomplexes

Respiratory supercomplexes may co-exist in the cristae membrane with single OXPHOS complexes. Among the many different types of supercomplexes, ones containing complex I monomer, complex III dimer, and one or more units of complex IV form the most abundant supercomplex- SC I+III₂+IV_1-2. This supercomplex is also known as 'respirasomes' because it can autonomously carry out respiration in the presence of ubiquinone and cytochrome c.

In addition, there may exist supercomplexes of various other compositions and stoichiometries whose abundance and composition may vary among organisms and tissues depending on the metabolic and physiological conditions. For instance, complex I has an unstable structure and may dissociate into individual protein subunits. The stability of complex I depends on its association with other complexes such as complex III dimer in SC I+III₂. Genetic mutations that lead to the loss of complex III are correlated to the loss of complex I and associated supercomplexes.

Complex III also forms a stable association with one or multiple units of complex IV in supercomplex(III₂+IV_1-2). Such simpler supercomplexes are abundant in organisms like Saccharomyces cerevisiae that do not express complex-I. Such organisms mainly comprise SC III₂+IV₁ and III₂+IV₂ in addition to complex II that serves as the only entry point for electrons into the electron transport chain.

The respiratory supercomplexes may be organized into even larger complexes called megacomplexes or respiratory strings. Human respiratory SCI+III₂+IV could form a circular MCI₂+III₂+IV₂. The function of these high-order complexes remains an area of research.

The electron chain complexes are crucial components to couple redox reactions with ATP synthesis.

They can be present on the inner mitochondrial membrane as discrete entities with mobile electron carriers transporting the electrons between two neighboring complexes.

Alternatively, a phospholipid called cardiolipin acts as molecular glue, organizing different combinations of individual complexes into respiratory chain supercomplexes or even megacomplexes.

In a supercomplex, the distance between neighboring complexes is reduced compared to individually arranged complexes.

This allows mobile electron carriers to diffuse quickly from one complex to another in the supercomplex assembly, improving their electron transfer and proton-pumping efficiencies.

In cells with high-energy demand, a respiratory supercomplex can thus generate a large proton-motive force for upregulating the ATP production.

In addition, supercomplexes also play a role in regulating the reactive oxygen species or ROS.

The toxic superoxide radicals are produced when reactive sites, such as iron-sulfur clusters, remain exposed to oxygen.

In a supercomplex assembly, the reactive sites become insulated by the protein environment and become inaccessible to oxygen, thereby preventing excessive ROS formation.