Complex I structure, open and closed states, and quinone-site inhibitors
Complex I oxidises NADH and passes electrons to quinone, producing quinol for complex III.6 Kühlbrandt (2015) described the mitochondrial enzyme as about 1 megadalton, larger than complexes III and IV together.1 Whether supercomplexes channel quinone to complex III remains disputed.67
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Size and subunit makeup
Kühlbrandt (2015) noted that mitochondrial complex I, at about 1 megadalton, is far larger and has more subunits than complexes III and IV put together.1 A mammalian X-ray structure was then missing. Structures existed for the yeast Yarrowia lipolytica and for the smaller Thermus thermophilus enzyme. Comparing them, Kühlbrandt reported that the 14 conserved core subunits share essentially one structure, with three proton antiporter modules in the membrane and eight iron-sulfur clusters in the matrix arm.2 Morelli and colleagues (2019) counted as many as 45 polypeptides in mammals and stressed that assembly depends on chaperones.3
Open and deactive states
Sousa, Mills, Vonck and Kühlbrandt (2016) sorted bovine respirasome particles into classes. In one class the matrix arm of complex I had moved away from the supercomplex centre by a rotation of 3 to 4 degrees. They linked this to active and deactive complex I structures from Zhu and colleagues (2016), which differ by a similar matrix arm movement.4 Letts and colleagues (2019) separated three open states by standard classification. They then classified by the angle between peripheral and membrane arms and obtained at least six open structures.5
Quinone exchange and channeling
Fedor and Hirst (2018) added an alternative quinol oxidase to heart mitochondrial membranes. Quinol from complex I was reoxidised faster outside the supercomplex than by complex III inside it. They concluded that quinone and quinol diffuse freely and that channeling does not occur.6 Letts and colleagues (2019) tested a supercomplex preparation with a quinone analogue and no added cytochrome c. Some NADH oxidation continued with 10 μM analogue, which they read as slow exchange with the bulk pool.7 Brzezinski, Moe and Ädelroth (2021) drew a consequence from Fedor and Hirst: supercomplex formation alone would not lower the fraction of reduced ROS-forming sites at complex I.8
Bacterial counterparts
Kühlbrandt (2015) described the mitochondrial enzyme as having about three times as many subunits as its bacterial ancestor. Most functions of the extra subunits are unknown, and many may act in assembly or regulation.2 Martin (2025), working through ATP yields in Escherichia coli, noted that the bacterium has a proton-pumping complex I (nuo) and also an alternative, ndh, that pumps no protons per NADH. Expression of these alternatives responds to oxygen, so the real ATP yield can fall below the maximum estimate.9
At a molecular mass of ~1 megadalton (MDa), mitochondrial complex I is far larger and has more subunits than complexes III and IV put together.
Kühlbrandt W, 2015 · Structure and function of mitochondrial membrane protein complexes · open at passage 22the 14 conserved core subunits have essentially the same structure in both, including three proton antiporter modules in the membrane and eight iron-sulfur clusters in the matrix arm.
Kühlbrandt W, 2015 · Structure and function of mitochondrial membrane protein complexes · open at passage 22Structures of active and deactive states of complex I have been recently presented, which differ by a similar movement of the matrix arm (Zhu et al., 2016).
Sousa JS, Mills DJ, Vonck J, Kühlbrandt W, 2016 · Functional asymmetry and electron flow in the bovine respirasome · open at passage 16Our results demonstrate that quinone and quinol diffuse freely in and out of supercomplexes: substrate channeling does not occur
Fedor JG, Hirst J, 2018 · Mitochondrial Supercomplexes Do Not Enhance Catalysis by Quinone Channeling · open at passage 0in mammals it is formed by as many as 45 polypeptides and its assembly needs an unknown number of chaperones
Morelli AM, Ravera S, Calzia D, Panfoli I, 2019 · An update of the chemiosmotic theory as suggested by possible proton currents… · open at passage 29Focus-Revert-Classify Strategy Results in at Least Six Different CI Open Structures
Letts JA, Fiedorczuk K, Degliesposti G, Skehel M, Sazanov LA, 2019 · Structures of Respiratory Supercomplex I+III<sub>2</sub> Reveal… · open at passage 28When 10 μM DQ was added, some NADH oxidation was maintained even in the absence of added cyt c
Letts JA, Fiedorczuk K, Degliesposti G, Skehel M, Sazanov LA, 2019 · Structures of Respiratory Supercomplex I+III<sub>2</sub> Reveal… · open at passage 20formation of supercomplexes that involve complex I would not per se result in decreasing the fraction of reduced ROS-forming sites at complex I.
Brzezinski P, Moe A, Ädelroth P, 2021 · Structure and Mechanism of Respiratory III-IV Supercomplexes in Bioenergetic… · open at passage 101Note that E. coli possesses an alternative to complex I that does not pump (ndh; 0H+ per NADH; [42])
Martin WF, 2025 · ATP requirements for growth reveal the bioenergetic impact of mitochondrial… · open at passage 9