Structure of the mitochondrial respirasome (electron transport complexes)

The membranes of bacterial cells and mitochondria contain a series of complexes that catalyze the oxidation of NADH. A lengthy electron transport chain leads eventually to the reduction of oxygen to water. Electrons lose energy as they pass down the chain and this is coupled to the transport of protons (H⁺) from one side of the membrane to the other. This proton gradient is used to drive ATP synthesis by the ATP synthase complex. The mechanism of making ATP is chemiosmosis but the pathway is often called oxidative phosphorylation or respiration.

The discovery of chemiosmosis (Chemiosmotic Theory) is one the few examples of a genuine paradigm shift. It is largely due to the work of Peter Mitchell [Ode to Peter Mitchell].

Each of the three complexes (I, III, and IV) are made up of a number of protein subunits and various cofactors. It has long been assumed that they associate in the membrane to form a large supercomplex and recent advances have confirmed this assumption. (See Electron transport supercomplexes in the mitochondria.)

The latest effort comes from a group of European labs that looked at the mitochondrial membranes of a single-cell green alga (Chlamydomonas reindardtii) using a technique called cryo-electron tomography (Waltz et al., 2025).

The respirasome supercomplex consists of two units of Complex I (blue), two dimers of Complex III (four units, green), and six individual units of Complex IV at three different symmetrical positions (P, M, and D, brown). Thus the overall stoichiometry is I₂,III₄,IV₆. The composition of supercomplexes in other species is probably a bit different.

The respirasome complexes are located in the "flat" regions of the mitochondria membranes where they pump protons into the narrow space between the membranes creating a high concentration of protons. The ATP synthase complexes are clustered together and they distort the membrane to create the ends of the mitochondrial cristae. You can think of them as stacks of pancakes.

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Image credit: The first image is a modified version of Figure 14.6 from Moran et al. Principles of Biochemistry, 5th edition. The other images are from Waltz et al. (2025).

Waltz, F., Righetto, R.D., Lamm, L., Salinas-Giegé, T., Kelley, R., Zhang, X., Obr, M., Khavnekar, S., Kotecha, A. and Engel, B.D. (2025) In-cell architecture of the mitochondrial respiratory chain. Science 387:1296-1301. [doi: 10.1126/science.ads8738].