Squeezing Those Electrons For All They've Got

How respiratory complex I harnesses electron transfer from NADH to quinone to power the mitochondrial battery.

Energy- we can't live without it, we can't make it ourselves, and we use all sorts of complex technologies to harvest and store it. Solar power is reaching a crisis as we realize that it isn't going to work without storage. Life faced similar crises billions of years ago, and came up with core solutions that we know now as the chemical transformations of photosynthesis and metabolism. Plants make storage compounds from sunlight, which we in turn eat for energy, transforming them into a series of currencies from short- to long-lived, such as NADH, protons, ATP, glucose, and finally, fat.

Within us, the mitochondrion is the engine, not making energy, but burning it from the food we eat. The core citric acid cycle disassembles the reduced carbon compounds that serve as our food and longer-term storage compounds into oxidized CO2 and energy carriers NADH, FADH. While used widely in the cell for specialized needs, these compounds are not our core energy stores, and are generally sent to the electron transport chain for transmutation into a proton gradient that serves as the battery of the mitochondrion, which is in turn used to synthesize our general energy currency, ATP. ATP is used all over the cell for general needs, including the synthesis of glucose, glycogen, and fat as needed for longer term storage.

The discovery of the proton battery was one of the signal achievements of 20th century biochemistry, explaining how mitochondria, and bacteria generally, (from which they evolved), handle the energy harvested via the electron transport chain from food oxidation in an organized and efficient way, without any direct coupling to the ATP synthesis machinery. The electron transport chain is a series of protein complexes embedded in the innermost mitochondrial membrane that receive high-energy electrons from NADH / FADH made in the matrix through the citric acid cycle and use them to pump protons outwards. Then the ATP synthetase enzyme, which is another highly specialized and interesting story, uses the energy of those protons, flowing back in through its rotary structure, to synthesize ATP. The proton gradient is short-lived, a bit like our lithium batteries, continually needing to be recharged- a key form of storage, but just one part of a larger energy transformation system.

A recent pair of papers from the same lab, capitalizing on the new technologies of atomic structure determination, describe in new detail the structure of respiratory complex I, which is a huge complex of 45 proteins that receives NADH, conducts its two electrons to ubiquinone, and uses that energy to pump out four protons from the mitochondrial matrix. Not all questions are answered in these papers, but it is a fascinating look into the maw of this engine. Ubiquinone (often abbreviated as Q) is then later taken up by another respiratory complex that squeezes out a few more protons, while transferring the electrons to cytochrome C, which goes to yet another respiratory complex that squeezes out a final few protons.  Like in our macroscopic world, a lot of complicated machinery is needed to keep a power system humming. 

The complex hinges literally on the Q binding site, which is at the elbow between the intracellular portion that binds NADH, and the series of proteins that all sit in the membrane. When Q binds, the bend is larger, (called the closed form), and when it leaves, the bend is smaller (called the open form). The electron path through the paddle is reasonably well understood, going through several iron-sulfur and flavin mononucleotide complexes that have special overlapping quantum tuning to allow extremely efficient electron transport. The key to the whole system is how the transfer of electrons from NADH through the paddle domain down to Q, which protonates it to QH2 and makes it leave to travel through the membrane to its other destinations, is coupled with a long-range physical and electrostatic shift through the rest of the complex to run the proton pump cycle. 

Structure of complex I, emphasizing the electron path in the paddle (upper right) and the many possible proton conduction paths in the membrane-resident part of the complex (bottom). The Q binding site is shown in brown at the elbow. Each protein subunit is named and given a distinct color. A conductive "wire" through the middle of the membrane components is isolated from the solvent, but connected to each membrane side with dynamically gated pathways. Whether these gates have more of a physical character or an electrostatic character, or both, remains uncertain.

The membrane domain, made up of several similar proteins all side-by-side, seems to have a sort of wire running through the middle, made up of charged amino acid side chains and water molecules, capable of conducting protons parallel to the membrane. It also has specific proton conduction paths within each subunit that provide the possible entry and exit paths for protons getting pumped from the interior outwards. The authors propose that there is a sort of hokey-pokey going on, where one bent form (the open form, with Q ejected) of the machine exposes the matrix-side proton channels, while the other bent form (closed form, with Q present) closes those channels and opens a corresponding set of four channels on the other side that let those same protons out to the cell. The internal wire, they propose, may possibly redistribute the protons to buffer the input channels. Or it might even allow all four to exit on the last, fourth pump complex. In any case, this in essence is the core of biological pump designs, opening channels in one direction to capture protons from one side, (by diffusion), and then executing a switch that closes those and opens ports to the other side, again using diffusion to let them go, but in a new direction. It is the physical cycle that translates energy into chemical directionality, aka pumping.

Proposed mechanism, with the insertion or ejection of Ubiquinone Q dictating the  proton channel accessibility along the membrane proton pump subunits of complex I. Protons enter from the mitochondrial matrix in the blue structures (closed), and exit via the other side in the green structures (open).

Closeup of one of the membrane proton pump segments, showing the dynamic formation of one proton conduction channel in the "open" state (left) vs the closed state (right, circled). The somewhat dramatic turning of the center protein helix carrying residues M64 and F68 opens the way

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Rank	Country	Total Cases	New Cases	Total Deaths	New Deaths	Total Recovered	Active Cases	Serious, Critical	Tot Cases/1M	Deaths/1M
1	USA	27,798,163	+93,759	479,726	+3,219	17,631,858	9,686,579	21,446	83,682	1,444
83	China	89,720	+14	4,636	0	84,027	1,057	18	62	3