Continue Your Comparison of Electron Transport and Chemiosmosis

Chemiosmosis

Ultimately, chemiosmosis or ATP synthesis occurs at complex V or ATP synthase via an endergonic reaction induced by the electrochemical gradient, resulting in the movement of protons through the ATP synthase (complex V) into the mitochondrial matrix, and transferring an inorganic phosphate to ADP.

From: Clinical Bioenergetics , 2021

Oxygen

Andrew Lumb MB BS FRCA , in Nunn and Lumb's Applied Respiratory Physiology , 2021

Aerobic energy production

The aerobic pathway permits the release of far greater quantities of energy from the same amount of substrate, and is therefore used whenever possible. Under aerobic conditions, most reactions of the glycolytic pathway remain unchanged, with two very important exceptions. The conversion of glyceraldehyde-3-phosphate to 3-phosphoglyceric acid occurs in the mitochondrion, when the two NADH molecules formed may enter oxidative phosphorylation (see later discussion) rather than producing lactic acid. Similarly, pyruvate does not continue along the pathway to lactic acid but diffuses into the mitochondria and enters the next stage of oxidative metabolism.

The citric acid (Krebs) cycle occurs within the mitochondria, as shown inFigure 10.13. It consists of a series of reactions to reduce the length of the carbon chain of the molecules before adding a new two-carbon chain (acetyl CoA) derived from glycolysis. During these reactions, six molecules of carbon dioxide are produced (for each molecule of glucose), along with a further eight molecules of NADH and one molecule of FADH₂. Therefore in total, each glucose molecule yields 12 hydrogen ions bound to either NAD or FAD carrier molecules.

The scheme shown inFigure 10.13 also accounts for the consumption of oxygen in the metabolism of fat. After hydrolysis, glycerol is converted into pyruvic acid, while the fatty acids shed a series of two-carbon molecules in the form of acetyl CoA. Pyruvic acid and acetyl CoA enter the citric acid cycle and are then degraded in the same manner as though they had been derived from glucose. Amino acids are dealt with in similar manner after deamination.

Oxidative phosphorylation is the final stage of energy production, and again occurs in the mitochondria. ³⁶ Hydrogen ions are forced to move along a chain of enzymes, arranged in rows along the cristae of the mitochondria, against their concentration gradient. This process, called chemiosmosis, involves the electron donor molecules NADH or FADH ₂, generated from the citric acid cycle and other metabolic pathways, modifying the electrical charge of the mitochondrial enzymes. This forces the positively charged protons across the mitochondrial membrane. At the end of the mitochondrial chain the protons reach a high enough energy level to combine with molecular oxygen at cytochrome a₃, forming water.Figure 10.14 shows the transport of electrons along the chain, forcing the hydrogen ions to move against their concentration gradient. Three molecules of ATP are formed at various stages of the chain during the transfer of each hydrogen ion. The process is not associated directly with the production of carbon dioxide, which is formed only in the citric acid cycle.

Cytochromes have a structure similar to haemoglobin, with an iron-containing haem complex bound within a large protein. Their activity is controlled by the availability of oxygen and hydrogen ions and the local concentrations of ATP relative to ADP and phosphate. ^{36 , 37} Different cytochromes have different values for P₅₀, and may act as oxygen sensors in several areas of the body. There is evidence for an interaction between nitric oxide and several cytochromes, with nitric oxide forming nitrosyl complexes in a similar fashion to its reaction with haemoglobin (page 148). ³⁸ It is postulated that nitric oxide or nitric oxide-derived nitrosyl compounds may play an important role in controlling oxygen consumption at a mitochondrial level. High levels of endogenous nitric oxide, for example during sepsis, may produce sufficient inhibition of cytochrome activity, and therefore oxygen consumption, to contribute to the impaired tissue function seen in vital organs such as the heart. ³⁸ The reduction of oxygen to water by cytochrome a₃ is inhibited by cyanide.

Membrane Transport | The Mitochondrial Permeability Transition Pore☆

Michela Carraro , Paolo Bernardi , in Encyclopedia of Biological Chemistry (Third Edition), 2021

Chemiosmosis, Mitochondrial Channels and the PT

The 4 basic postulates of chemiosmosis are (1) that the membrane-located ATPase reversibly couples the translocation of protons across the membrane to the flow of anhydro-bond equivalents between water and the couple ATP/(ADP + Pi); (2) that the membrane-located respiratory chain catalyzes the flow of reducing equivalents, coupling reversibly the translocation of protons across the membrane to the flow of reducing equivalents during oxido-reduction; (3) that the mitochondrial inner membrane has specific carriers allowing anion-OH ⁻ and cation-H⁺ exchanges that regulate the pH and osmotic differential across the membrane, and permit the flux of essential metabolites without collapse of the membrane potential; and (4) that the systems of the first three postulates are located in a specialized coupling membrane which has a low permeability to protons and to anions and cations generally (Mitchell, 2011). The 4th postulate was widely (and erroneously) implied to mean that the inner membrane did not possess cation channels. Given that this view prevailed as late as the 1990s, it comes as no surprise that the PTP, at an estimated diameter of 3 nm, did not attract too much interest in Bioenergetics. Things have changed dramatically over the last 30 years, following the demonstration that the inner mitochondrial membrane does possess cation channels that are expectedly tightly regulated; and that a PT can occur in cells, tissues and organisms where it plays a role in cell death, and possibly in Ca²⁺ homeostasis (Szabó and Zoratti, 2014).

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Organellar Ion Channels and Transporters

Jin O-Uchi , ... Shey-Shing Sheu , in Cardiac Electrophysiology: From Cell to Bedside (Seventh Edition), 2018

Overview of Mitochondrial Bioenergetics and Mitochondrial Membrane Potential

The most prominent contribution of mitochondria to cellular metabolism is based on their capacity to generate ATP through the tricarboxylic acid (TCA) cycle and OXPHOS through the ETC, which is a concerted series of redox reactions catalyzed by four multisubunit enzymes embedded in the IMM (complex I–IV) and two soluble factors, cytochrome c (cyt c) and coenzyme Q₁₀ (CoQ₁₀) that function as electron shuttles within the mitochondrial intermembrane space (IMS) (see Fig. 7.1B) (see "Historical Overview of Mitochondrial Ion Channel/Transporter Research" and "Proton Fluxes and Uncoupling Proteins "). In eukaryotic cells, more than 90% of the total intracellular ATP is generated by mitochondria. The main driving force of OXPHOS is known as "chemiosmosis" and is generated by the proton (H ⁺) movement across IMM that creates a membrane potential (ΔΨ _m , negative in the matrix) and a pH gradient (ΔpH, alkaline in the matrix). Chemiosmosis is the movement of ions across a selectively permeable membrane, down their electrochemical gradient (proton motive force: Δp), which is determined by both ΔΨ _m , and ΔpH components across the IMM (Δp = ΔΨ _m + ΔpH). The chemiosmotic hypothesis was first proposed by Peter D. Mitchell in 1961. ¹³ The basic assumption of the chemiosmotic theory is derived from the important observation that the IMM is generally impermeable to ions, but it keeps the permeability of H⁺. The composition of the OMM is similar to those of the sarcolemma (SL) and ER/SR in eukaryotic cells, whereas the IMM does not possess cholesterol but has a unique dimeric phospholipid, cardiolipin, which is a typical composition for bacterial membranes. Cardiolipin has a unique ability to interact with proteins including several mitochondrial respiratory chain complexes (I, III, IV, and V) and to support their activities ¹⁴ while also contributing to the maintenance of the structure of cristae, which enhances the efficiency of ETC activity, possibly through the facilitation of the formation of super complexes of the respiratory chain at the IMM. ¹⁵ The unique structure of cardiolipin serves as a H⁺ trap at the IMS near the IMM, maintains the pH change near the IMM, and efficiently pools H⁺ or releases H⁺ to the mitochondrial ATP-synthase (complex V) at IMM (see Fig. 7.1B). ^13,14 Interestingly, the IMM and OMM not only have different phospholipid compositions but also show different protein-to-lipid ratios (about 1 for OMM and about 4 for IMM). This may allow the proteins at the IMM to possess enzymatic and/or transport functions compared to those at the OMM, thereby making the IMM much less permeable to ions and small molecules than the OMM, which also provides the cellular compartmentalization between the mitochondrial matrix and cytosol. As shown in Fig. 7.1B, complexes I, III, and IV are engaging with the translocation of H⁺ from the matrix to the IMS, which establishes ΔΨ _m and ΔpH (i.e., Δp). Therefore ΔΨ _m is usually highly negative (around −180 mV) compared with the resting potential at plasma membranes. Finally, according to the above mechanisms, this large driving force for H⁺ influx (Δp) is used by complex V to produce ATP (see Fig. 7.1B). Other important roles for Δp in addition to ATP synthase at the IMM is that (1) ΔpH drives pyruvate transport through the pyruvate carrier (PYRC) into the matrix, (2) ΔpH drives Pi transport through the Pi carrier (PIC) into the matrix, and (3) ΔΨ _m drives ATP/ADP exchange through the adenine nucleotide translocator (ANT) (see Fig. 7.1A and B).

As mentioned in "Historical Overview of Mitochondrial Ion Channel/Transporter Research," Ca²⁺ uptake into the mitochondrial matrix stimulates ATP synthesis (see Fig. 7.1A). At the resting state, the electrochemical driving force for Ca²⁺ uptake is also provided by ΔΨ _m across the IMM. For MCU, Ca²⁺ is taken into the mitochondrial matrix down its electrochemical gradient without transport of another ion. Basically, for each Ca²⁺ transported through MCU, there is a net transfer of two positive charges into the matrix resulting in a drop of ΔΨ _m , which is energetically unfavorable. However, the Ca²⁺-stimulated respiration not only compensates the loss of ΔΨ _m by the efflux of H⁺ via ETC but also produces a net gain of ATP. In addition, multiple Ca²⁺ efflux mechanisms work in concert to expedite a transient and an oscillatory nature rather than a tonic and a steady state change of matrix [Ca²⁺] ([Ca²⁺]_m).

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THE CHEMIOSMOTIC PROTON CIRCUIT

In Bioenergetics 2, 1992

(a) Is there a class of membrane active agents which can stimulate respiration without lowering Δp?

Selected references Rottenberg 1986, Schonfeld et al., 1989

The action of protonophores, 'uncouplers', on the proton circuit should be relatively straightforward: an increase in proton conductance causes a lowering of Δp and a relaxation of respiratory control. Nevertheless, there have been reports that some fatty acids, gramicidin derivatives and local anaesthetics increase state 4 respiration without a detectable lowering of Δp. These agents have been termed 'decouplers' (Rottenberg, 1986 ). These results are not readily explained by delocalized chemiosmosis since they suggest that the respiratory chain complexes can in some way be locally 'short-circuited' in a way which does not involve the proton circuit or affect the measurable proton conductance of the membrane ( Fig. 4.18). However, in the 'delocalized' paradigm only a slight decrease in Δp appears necessary to produce a large stimulation of respiration (Figs 4.14, 4.15). Before 'decouplers' become generally accepted it would be necessary to eliminate possible artifacts such as a 'decoupler'-induced swelling of the mitochondrial matrix which might distort the calculations of Δp since these require an accurate knowledge of the matrix volume (Fig. 4.3). It is notable also that other research groups find that the proposed 'decoupler' long-chain fatty acids behave as typical protonophores, acting to increase C _MH⁺.

Figure 4.18. Localized and delocalized proton circuits.

'Localized' theories propose that there are local circuits between individual respiratory chain assemblies and ATP synthases. There would be a significant 'resistance' to be crossed for protons leaving this microdomain, which would be detected as a discrepancy in the respiratory stimulation corresponding to a given depression in Δp (detected outside the domain) when FCCP was added or when ADP was added: Δp would have to drop further with FCCP than with ADP (see text).

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Thermodynamics of Biological Reactions

H.W. Doelle , in Bacterial Metabolism (Second Edition), 1975

Conservation of Energy of Oxidation as ATP Energy

The conservation of energy from oxidoreduction reactions occurs in two ways (7).

1. The oxidation of a catabolite is followed by the reduction of a biosynthetic intermediate. The transfer of reducing equivalents is carried out by an intermediate oxidoreduction carrier, e.g., NAD⁺ or NADP⁺ (see p. 46). The general scheme of such a system is

2. The oxidation of a catabolite is followed by an energy transfer to an endergonic biosynthetic reaction, whereby ATP is synthesized and again hydrolyzed

In both cases catabolic and biosynthetic reactions are coupled via oxidoreduction mechanisms and both result in the production, conservation, and release of energy in the form of the shuttle service for phosphate groups, as described in the previous section. We therefore divide all coupled energyforming oxidoreduction reactions into two categories: (1) oxidative phosphorylation and (2) substrate level phosphorylation.

OXIDATIVE PHOSPHORYLATION.

During the oxidation of a catabolite, electrons are set free that must be accepted by an oxidizing agent. If the catabolite is assumed to be molecular hydrogen and the oxidizing agent molecular oxygen, the potential difference between both would be 0.81 – (−0.42) = 1.23 V, which is equivalent to ΔF° = 57 kcal (see p. 21). In the biological cell, however, molecular hydrogen is rarely a catabolite, as the catabolite transfers its hydrogen first to a hydrogen carrier, e.g., NAD⁺ or NADP⁺, and reduces this carrier; the cell then oxidizes NADH + H⁺ or NADPH + H⁺. The potential difference is thus reduced to 1.12 V or a ΔF° = −52 kcal. This amount of energy would certainly damage or destroy the cell if released as heat. The cell therefore has an arrangement by which this biochemical reaction is subdivided in a number of small individual energy steps. In other words, NADH + H⁺ and NADPH + H⁺ are unable to react directly with molecular oxygen but do react with a number of individual intermediates. This stepwise reduction of the total potential energy through a chain of redox systems is made possible by a number of coupled reactions. The cell is thus able to conserve part of the energy as chemical energy (ATP). This stepwise electron carrier system is called the "respiratory chain" (Fig. 1.6).

Fig. 1.6. Sequence of redox systems in the respiratory chain

[from Karlson (8)].

Although the electron transport mechanisms in mammalian systems are well studied, the knowledge of bacterial electron transport mechanisms has lagged well behind. The main reason for this is the great diversity of metabolic types among bacteria, which provides an even greater diversity in composition of the electron transport chains. A generalized scheme was well summarized by Dolin (4) (Fig. 1.7). The donated hydrogen is transferred from the substrate to NAD⁺, which itself then donates electrons to the cytochrome system via a flavoprotein (FP). The identity and number of cytochrome components vary from species to species and also with growth conditions. Bacteria may contain such pigments as the cytochromes a, a₃, b, c, and c₁ and others in a number of combinations. Some of the cytochromes have only been observed in bacteria. The main difference between the mammalian and the bacterial cytochrome systems, however, seems to be the presence of several oxidases in bacteria.

Fig. 1.7. Generalized electron transport system.

The possible pathway among the different bacteria could be summarized as shown in Fig. 1.8 (16). The cytochromes of the bacterial systems, which are attached to insoluble particulate matter within the cell, can have very high turnover rates. The numerous combinations of cytochrome components in different bacteria has led to the conclusion that the only requirement is for a mixture of several cytochromes with appropriately separated redox potentials. The most common ones are presented in Table 1.3, together with some electron donors, acceptors, and carriers. After the enzyme-catalyzed dehydrogenation of a substrate, two electrons pass through the components of the electron transport chain. This chain forms a transport sequence in which there occurs a stepwise increase in potential from that of NADH + H⁺/NAD⁺ to that of the oxygen electrode. Most substrates (e.g., lactate) are electromotively passive. In the presence of the appropriate dehydrogenase, the oxidation of the substrate is catalyzed and the resulting two-component system (e.g., lactate–pyruvate) establishes the potential of the lower end of the electron transport chain. The oxidized substrate (e.g., pyruvate) may enter a metabolic system while the released electrons proceed independently along the transport system.

Fig. 1.8. Possible variations in the electron transport system of microorganisms.

TABLE 1.3. Some Electrode Potentials of Biological Interest ^a

Couple	E 0' (V at pH 7.0)
2 H2O ⇌ O2 + 4 H+ + 4 e	+0.816
NO2 − + H2O ⇌ NO3 − + 2 H+ + 2 e	+0.421
H2O2 ⇌ O2 + 2 H+ + 2 e	+0.295
Cyt. a3 2+ ⇌ cyt. a3 3+ + 1 e	+0.285
Cyt. a2+ ⇌ cyt. a3+ + 1 e	+0.290
Cyt. c2+ ⇌ cyt. c3+ + 1 e	+0.250
Succinate ⇌ fumarate + 2 H+ + 2 e	+0.031
H2 ⇌ 2H+ + 2e (pH 0)	0.0
Cyt. b2+ ⇌ cyt. b3+ + 1 e (pH 7.4)	−0.040
Lactate ⇌ pyruvate +2H+ + 2 e	−0.19
FADH + H+ ⇌ FAD+ + 2 H+ + 2 e	−0.22
NADH + H+ ⇌ NAD+ + 2 H+ + 2 e	−0.32
NADPH + H+ ⇌ NADP+ + 2 H+ + 2 e	−0.324
H2 ⇌ 2 H+ + 2 e	−0.414
Glyceraldehyde 3-P + H2O ⇌ 3-phosphoglycerate + 3 H+ + 2 e	−0.57
α-Ketoglutarate + H2O ⇌ succinate + CO2 + 2 H+ + 2 e	−0.673
Pyruvate + H2O ⇌ acetate + CO2 + 2 H+ + 2 e	−0.699

a

From Dolin (4).

From Table 1.3 and Fig. 1.9, it can be seen that glyceraldehyde, α-ketoglutaric acid, and pyruvic acid—carbonyl and carboxyl compounds—are the most potent electron donors. Electrons from substrates usually enter the electron transport system through a carrier the potential of which lies in the vicinity of, or higher than, the potential for the substrate dehydrogenation. In the presence of the appropriate catalyst, electron flow will take place from the system of lower potential to the system of higher potential (more positive). The greater the difference in voltage, the farther the reactions will go toward completion.

Fig. 1.9. Comparison of the electrode potentials of coenzymes and substrate systems (4).

The importance of the respiratory chain, with its redox cascades, lies in the possibilities of transforming the free energy obtained in every step into chemical energy by forming and storing ATP. The yield of ∼P thus depends on the ΔF of the reaction and on the number of steps available for energy conservation. If, for example, 1 mole NADH + H⁺ reacts with 0.5 mole O₂, 52 kcal will be set free. It has been demonstrated above that for the formation of 3 moles ATP from ADP and inorganic phosphates only about 21 kcal are necessary; thus, a 40% energy conservation would be obtained. Figure 1.8 also indicates that substrates that are dehydrated not by NAD⁺ but through flavoproteins (e.g., succinate), or even cytochrome c, must obtain less than 3 moles ATP. Wherever oxygen is the final electron acceptor, the results of such energetical calculations are usually expressed as P/O ratios. This ratio represents the equivalents of phosphate esterified per atom of oxygen taken up.

The key question in oxidative phosphorylation is still unsolved: what is the mechanism that leads from the release of free energy to the readily formed storage product ATP? At the moment there exist two main hypotheses.

1.

The Slater theory of a chemical coupling via energy-rich intermediates, which should go parallel to the substrate phosphorylation (see p. 32)

2.

The Mitchell theory of chemiosmosis, whereby it is necessary first to establish a difference in electrochemical concentration

The Slater theory states that the redox reaction is coupled with the formation of an energy-rich intermediate C ∼ A. These intermediates can be hydrolyzed by dinitrophenol, which explains the function of this chemical compound as respiratory chain uncoupler. The intermediate C ∼ A now transfers the energy-rich ∼A to a second compound, X, and

forms X ∼ A. This energy-rich intermediate could, if so required, transfer its energy immediately to an endergonic process, such as reversal of the respiratory chain (see aerobic chemolithotrophs) or osmotic work. It can also react further with inorganic phosphate, however, to form X ∼ P. This step can be intercepted by oligomycin, which explains the function of this compound as an uncoupling agent. The inorganic phosphate can now be transferred to ADP by X and ATP is formed.

The disadvantage of this hypothesis is that so far none of the proposed energy-rich intermediates have been found or isolated.

The Mitchell theory is based on the assumption that during the redox reactions of the membrane-bound enzymes, the H⁺ ions can only be formed outside and the OH⁻ ions only inside the membrane. As the H⁺ ions can be exchanged with the K⁺, OH⁻, and Cl⁻ ions, an electrochemical gradient develops that can do work. This gradient is thought to equilibrate at certain "coupling places" with the formation of energy-rich carrier. The energy of this carrier should be sufficient to attach the inorganic phosphate to ADP with the formation of ATP. The generation of a potential difference across the membrane, in other words, is the result of proton translocation (12, 15).

This theory depends solely on the assumption that there is an intact membrane structure, as is the case in higher organisms with mitochondria. In principle, it is the reverse of the process of active transport, the mechanism of which has still to be discovered. It is hoped that future research will clarify the problems of oxidative phosphorylation.

SUBSTRATE LEVEL PHOSPHORYLATION.

An oxidoreduction reaction with a large and negative free energy change can be coupled to ATP synthesis and therefore does not need a further hydrogen transfer from NADH + H⁺. Lehninger (11) demonstrated the foregoing by an actual reaction occurring in the cell as follows: The oxidation of an aldehyde to a carboxylic acid in aqueous solution is known to proceed with a large decline in free energy

In the cell, the oxidation of certain aldehydes takes place enzymatically in such a way that this energy is not simply lost as heat but is largely conserved. For example, 3-phosphoglyceraldehyde is oxidized to the acid 3-phosphoglycerate during glucose oxidation

This reaction does not take place in exactly this way but is coupled with the combination of one molecule of phosphate to one of ADP to form ATP.

The potential energy of the aldehyde group is transformed by the binding of an additional phosphate on to ADP, forming ATP. This conclusion is drawn from the free energy change in the reaction, which is approximately zero. The free energy decline of ∼7000 cal/mole from the aldehyde oxidation is absorbed in the formation of ATP from ADP and phosphate, which requires an input of 7000 cal/mole (see Table 1.4). This phosphate transfer occurs in two separate steps, each catalyzed by a separate enzyme. When the aldehyde R—CHO was oxidized by the first enzyme, a large

TABLE 1.4. Standard Free Energy of Hydrolysis of Some Energy-Rich Compounds ^a

Compound	ΔF° (cal/mole)
ATP (–ADP + orthophosphate)	7,000
ATP (–AMP + pyrophosphate)	8,000
Pyrophosphate (−2 orthophosphate)	6,000
Creatine phosphate	8,000
Phosphoenolpyruvate	12,000
Phosphoglyceryl phosphate	11,000
Acetyl-coenzyme A	8,000
Aminoacyl AMP	7,000

a

From Karlson (8).

part of the free energy decline normally occurring when aldehydes are oxidized was conserved in the form of the phosphate derivative of the carboxylic acid. In the second reaction, the carboxyl phosphate group of the 1,3-diphosphoglycerate, the free energy hydrolysis of which is substantially higher than that of ATP, is enzymatically transferred to ADP and ATP is formed. The energy of oxidation of the aldehyde has thus been conserved in the form of ATP by two sequential reactions, in which the high-energy phosphate derivative of a carboxylic acid is the common intermediate.

Uphill reactions, whereby ATP energy is utilized to do chemical work, are very similar and can be demonstrated in the reaction

$\begin{array}{ll}\text{glucose}+\text{fructose}\to \text{surose}+\text{water}& \Delta F^{\prime }=+5500\text{cal}/\text{mole}\end{array}$

If the sequence of reactions required are now dissected to analyze the energy changes, it is found that the energy-yielding process is the hydrolysis of ATP and the energy-requiring process is the formation of sucrose. Adenosine triphosphate is the common intermediate, linking the energy-yielding reaction and the energy-requiring synthesis of sucrose.

$\begin{array}{c}\text{RCHO}+{\text{HPO}}_4^{2-}\to {\text{2H}}^{+}+{\text{RCOOPO}}_3^{2-}\\ {\text{RCOOPO}}_3^{2-}+\text{ADP}\to {\text{RCOO}}^{-}+\text{ATP}\\ \text{ATP}+\text{glucose}\to \to \text{ADP}+\text{glucose}1-\text{phosphate}\\ \frac{\text{glucose}1-\text{phoshate}+\text{fructose}\to \text{\hspace{0.17em}sucrose}+\text{\hspace{0.17em}phosphate}}{\text{sum}:\text{RCHO}+\text{glucose}+\text{fructose}\to {\text{\hspace{0.17em}2H}}^{+}+{\text{RCOO}}^{-}+\text{sucrose}}\end{array}$

This overall equation shows that the energy yielded by oxidation of aldehyde to an acid was used to form sucrose from glucose and fructose.

A number of bacteria are able to form high molecular weight polyphosphates or metaphosphates. This process appears to be a form of "high-energy" phosphate storage. This polyphosphate is formed solely from the terminal phosphate group of ATP.

The division of the bacteria into aerobes and anaerobes cannot be rigidly maintained from the point of view of comparative biochemistry, although it still plays an important role in bacterial nutrition and classification. Among the chemosynthetic bacteria in general, those which reduce inorganic sulfur compounds in various oxidation states are anaerobes, those which reduce nitrogen compounds in various oxidation states are facultative anaerobes, and those which oxidize reduced sulfur and nitrogen compounds are obligate aerobes.

It is possible to estimate the maximum energy available for biochemical use in the electron systems that may be encountered in anaerobes. However, information on phosphorylations coupled to the electron transport systems in anaerobic bacteria is very scattered and will be considered with the individual bacterial groups. In general, there is no justification for assuming that the electron transport systems of anaerobic bacteria differ in principle or even in any major way from that of aerobes. There is almost no difference in the cytochrome-dependent electron transport systems of facultative anaerobes when grown either aerobically or anaerobically, for both terminate in cytochromes. There are intermediate systems, in which the bacteria have become less dependent on cytochromes, that, as in aerobically growing Lactobacillaceae, are completely independent of cytochromes. Systems in obligate anaerobes will be discussed elsewhere (see Chapters 4 and 8). With all the presently available information, the tentative scheme for electron systems used by various microorganisms has been postulated by Dolin (4) and may function as a guide throughout bacterial metabolic studies (Fig. 1.10).

Fig. 1.10. General diagram of electron transport systems in aerobic, facultative anaerobic, and anaerobic bacteria.

Depending on the pathway under consideration in Fig. 1.10, 2[H] may represent (a) reducing equivalents, (b) reduced pyridine nucleotides, or (c) reduced flavoprotein. Cytochrome photooxidase is used by photosynthetic bacteria. Dolin provides the following definitions in relation to Fig. 1.10.

Obligate aerobes: Cannot grow in the absence of O₂. They presumably have no functional fermentative metabolism. Pathway of electron transport—a,b,c,d,e.

Facultative anaerobes: Can grow in the presence or the absence of O₂ (in absence of O₂ they use fermentative pathways). There are two groups:

1.

Cytochrome independent (e.g., lactic acid bacteria). Pathway of electron transport: aerobic—a,b,g; anaerobic—a,f (may be sole pathway of some representatives of this class).

2.

Cytochrome dependent (e.g., coliforms). Pathway of electron transport: aerobic—a,b,c,d,e; a,b,g; anaerobic—a,f; a,b,c,j (nitrate reduction); a,b,1.

Obligate anaerobes: Cannot grow aerobically. There are two groups:

1.

Cytochrome independent (e.g., Clostridium). Pathway of electron transport—a,f; a,b,g (not used under physiological conditions).

2.

Cytochrome dependent (e.g., Desulfovibrio). Pathway of electron transport—a,b,c,j (reduction of sulfur ions; step c obscure).

Such quinones as menaquinone seem to play an important role in electron transfer in Mycobacterium (1) and Corynebacterium (10).

These examples illustrate the general working principle by which ATP is the energy carrier in sequential reactions involving flow of phosphate groups in coupled reactions.

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Metabolism of Fat, Carbohydrate, and Nucleic Acids

Gerald Litwack Ph.D. , in Human Biochemistry, 2018

The Electron Transport Chain

For each molecule of NADH + H⁺ oxidized, the following products derive:

$\mathrm{NADH}+{\mathrm{H}}^{+}\to {\mathrm{NAD}}^{+}2{\mathrm{H}}^{+}2{\mathrm{e}}^{-}$

The electrons flow through the electron transport chain (ETC) to culminate in the production of ATP from ADP by ATP synthase at the terminal end of the chain. The overall process of the oxidation of coenzymes to produce ATP is called oxidative phosphorylation. NADH is an electron donor (see reaction above); these electrons flow through the electron transport chain (ETC) and end up by combining with molecular oxygen, an electron acceptor, to form water ("metabolic water"). The transport of electrons across the ETC generates free energy and this energy is used to produce ATP from ADP and inorganic phosphate by ATP synthase at the end of the chain. Protons are pumped from the mitochondrial matrix across the inner mitochondrial membrane to the intermembrane space, creating an electrical gradient and a pH gradient ( chemiosmosis ). There are more positive charges on the outer membrane than inside and, correspondingly, there is a lower pH on the outer membrane than inside. Oxidation is coupled to phosphorylation by the proton gradient and electron transport provides the energy to produce ATP.

Because the conversion of succinate to fumarate, catalyzed by succinic dehydrogenase, utilizes FADH ₂ and the oxidation of FADH₂ to FAD occurs at complex II, one step beyond complex I where protons from NADH enter, the oxidation of FADH₂ produces one less ATP (two ATP) than NADH + H⁺ (three ATP) because the overall free energy change from FADH₂ is less than that from NADH. The electron transport chain is shown schematically in Fig. 14.19.

Figure 14.19. Drawing of a hypothetical electron transport chain. There are four protein complexes labeled I, II, III, and IV. A portion of complex I is located in the mitochondrial matrix and the other portion is embedded in the inner mitochondrial membrane. The last member of the chain is the enzyme, ATP synthase. Hydrogen ions from NADH + H⁺ (at complex I) or from FADH₂ (at complex II) move into the intermembrane space along the outside of the inner membrane and are imported through a proton channel that is part of ATP synthase. The electrons from NADH or from FADH₂ flow along the complexes and finally interact with molecular oxygen to form water (along with protons). ATP synthase forms ATP from ADP + Pi with energy provided by electron transport. FADH ₂ , flavin adenine dinucleotide (reduced); CoQ, coenzyme Q or ubiquinone; Cyt c, cytochrome c; e⁻, electron.

Redrawn from http://www.teachersdomain.org/asset/tdc02_img_electronchai/. From Biology, Kenneth R Miller and Joseph Levine ©2002 by Pearson Education, Inc. Reproduced by permission of the publisher.

Converting all of the energy derived from the oxidation of NADH + H⁺ to NAD⁺, would lead to the synthesis of about seven molecules of ATP from ADP + Pi. The components of the ETC are the four complexes plus the terminal ATP synthase.

Complex I is NADH dehydrogenase (or, NADH-coenzyme Q reductase) that accepts electrons from NADH and serves as the link to the ETC, a link to glycolysis, fatty acid oxidation, and the TCA cycle. Complex I consists of about 30 protein subunits and has a molecular weight of about 850,000   Da; its cofactors are FMN (flavin mononucleotide) and about 7 Fe–S clusters (iron–sulfur clusters; up to 26 iron atoms are bound). It contains a substrate-binding site for NADH in the matrix portion and a binding site for CoQ in the lipid core. This complex transfers two electrons to coenzyme Q from NADH. After binding NADH, two electrons are transferred (as a hydride, H⁻) to FMN to generate NAD⁺ and FMNH₂. The electrons are transferred to a series of iron–sulfur clusters. One electron at a time is transferred to CoQ that can diffuse in the bilipid layer of the inner mitochondrial membrane because it contains an isoprenoid tail structure that has both hydrophobic and hydrophilic properties. The action of complex I results in the transport of protons from the matrix side of the inner mitochondrial membrane to the inter membrane space. Here, protons accumulate and generate a proton motive force (energy generated by transfer of protons and electrons across an energy-transducing membrane for use in chemical or other kinds of work). There are two H⁺ transported per electron.

Complex II is succinate dehydrogenase (or succinate-coenzyme Q reductase), the only enzyme of the TCA cycle that is membrane-bound and is the link in the ETC to the TCA cycle. This enzyme has four subunits with a molecular weight of 140,000   Da. Its cofactors are FAD (two subunits are FAD-binding proteins) and two of the subunits are Fe–S proteins. The Fe–S clusters are in various stoichiometries: of the three Fe–S units, one is 4Fe–4S, a second is 3Fe–4S, and the third is 2Fe–2S. Complex II has substrate-binding sites for succinate in the matrix portion and for CoQ in the lipid core. Complexes I and II both produce reduced Coenzyme Q (CoQH₂). Two electrons that are transported from NADH to CoQ are coupled to the transport of four protons across the membrane. First, succinate is bound; then a hydride (H⁻) is transferred to FAD, producing FADH₂ and fumarate. Electrons, one at a time, are transferred to the Fe–S units. Then, two electrons are transferred, one at a time, to CoQ to generate CoQH₂. The total free energy change is −72.4   kJ/mol; this is insufficient to drive the transport of protons across the inner mitochondrial membrane and accounts for nearly two ATP from FADH₂ compared to nearly three ATP from NADH.

Complex III is coenzyme Q reductase (also coenzyme Q-cytochrome c reductase) and transfers electrons from CoQH₂ for the reduction of cytochrome c . The complex contains one cytochrome c and two cytochrome b types. A larger portion of the structure of this protein dimer extends into the mitochondrial matrix and the rest extends outward into the mitochondrial inter membrane space. A Fe–S protein is contained in the enzyme, and it appears to have mobility within the structure that facilitates the transfer of electrons. The transport of electrons occurs through a complicated set of reactions called the "Q cycle." The result of the steps in the Q cycle is that two electrons are transported to cytochrome c1 and four protons, in total, are released into the inter membrane space. The electrons on cytochrome c1 are transferred to cytochrome c (the only soluble cytochrome) that carries electrons by diffusing into the inter membrane space carrying electrons from the cytochrome c1 heme to the Cu_A site of complex IV.

Complex IV is cytochrome c reductase (also known as cytochrome c oxidase) that transfers electrons from cytochrome c for the reduction of molecular oxygen to form water:

$4\mathrm{cyt}c({\mathrm{Fe}}^{2+})+4{\mathrm{H}}^{+}+{\mathrm{O}}_2\to 4\mathrm{cyt}c({\mathrm{Fe}}^{3+})+2{\mathrm{H}}_2\mathrm{O}$

It has up to 10 subunits and has a molecular weight of 162,000   Da. Complex IV has four prosthetic groups: heme a, heme a ₃ , Cu_A (copper A) and Cu_B (copper B). Cu_A is associated with cytochrome a and Cu_B is associated with cytochrome a ₃ . The enzyme contains two substrate-binding sites, one for cytochrome c (a single polypeptide chain of 13,000   Da whose prosthetic group is heme c ) in the inter membrane side and the other for O₂ in the matrix portion. Complex IV has two binding-sites, one for cytochrome c ₁ and the other for cytochrome a. The copper sites transfer electrons one at a time. Cytochrome c binds to Complex IV facing the side of the inter membrane space and transfers an electron to Cu_A that also is located on the portion of the protein in the inter membrane space. Cytochrome c, now oxidized, moves off of the enzyme into the inter membrane space. Cu_A transfers the electron to cytochrome a whose iron component is close to Cu_A on the enzyme. The electron is then passed on to the cytochrome a ₃, in close range toward the matrix side and then finally, the electron is moved to the "electron center," housing two electrons, and the binding of O₂ to the center occurs. Two protons are then bound and the entry of another electron leads to the dissociation of the O–O bond to generate Fe⁴⁺ in the metal (Fe) center. A fourth electron now forms a hydroxide which is protonated and leaves the center as H₂O.

ATP synthase is considered as the fifth complex (Complex V). It consists of two parts, F₁, the enzyme, and F₀, the proton channel (Fig. 14.19). F₁ is located outside of the membrane in the matrix, whereas F₀, the proton channel, is located in the inner membrane. These two structures are linked together by central and peripheral vertical structures (stalks). The catalytic center of F₁ is joined to a rotary mechanism of the subunits of the central stalk and to proton translocation. The enzyme, F₁, has five subunits (α, β, γ, δ, and ε) and the mitochondrial membranous proton channel has three main subunits (A, B, and C) and six additional subunits (d, e, f, g, F6, and AGL). The overall action of Complex V is to produce water from protons and electron energy and to produce ATP from ADP plus Pi.

Fig. 14.20 shows the TCA cycle in terms of the production of NADH from NAD, the sources of high-energy phosphate and respiratory chain (ETC).

Figure 14.20. The TCA cycle starting with acetyl CoA. The release of reducing equivalents is shown for each relevant step in the cycle, and these are used to reduce NAD⁺ to NADH + H⁺. The conversion of succinate to fumarate also produces 2   H but these are shuttled to coenzyme Q10 (Q; complex II) and give rise to two ATPs, whereas the other reducing equivalents each give rise to three ATPs (2   H is shuttled into complex I in each case). The respiratory chain (ETC) is shown with the production of ATP equivalent for each site.

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Respiration | Mitochondrial Calcium Transport: Historical Aspects

E. Carafoli , in Encyclopedia of Biological Chemistry (Third Edition), 2013

Early Findings on the Mechanism of the Uptake Process

In the wake of the early findings, mitochondrial Ca²⁺ transport rapidly became very popular, and became recognized as an alternative to ADP phosphorylation in the harvesting of the energy made available by the respiratory chain. For a long time, the findings on the process were interpreted within the framework of the chemical theory of energy transduction; in hindsight, it may seem surprising that the process was not immediately related to the then emerging chemiosmotic theory of energy transduction, for which it evidently provided essential support. Chemiosmosis, however, only crept into the field laboriously, and did not take it over until well into the 1960s. Meanwhile, numerous studies had established the essential phenomenology of the process; thus, the stoichiometry of Ca ²⁺ uptake to oxygen consumption was measured, finding that two Ca²⁺ ions were required to elicit the same extra consumption of oxygen elicited by one molecule of ADP, a finding that clearly confirmed the earlier conclusion by B Chance that the Ca²⁺/O stoichiometry in the transition from resting (state 4) to activated (state 3) respiration was 2–3 times the ADP/O stoichiometry. It also became clear that in the absence of phosphate the small amounts of Ca²⁺ that were taken up were maintained within mitochondria in a dynamic steady state, in which the leak of Ca²⁺ was balanced by its reuptake during the phase of resting respiration that followed the activated phase during which the pulse of Ca²⁺ had been taken up. It was an important finding, as it established the concept of a continuous cycling of Ca²⁺ across the mitochondrial membrane (the mitochondrial Ca²⁺ cycle), its long-term storage in the matrix only occurring when phosphate was also present and taken up. The finding that mitochondria could dynamically take up and release Ca²⁺ had obvious interest in the light of the emerging importance of Ca²⁺ in the regulation of cell activities, and placed mitochondria in a central position as potential regulators of cell function. At that time, however, an element in the scenario was still missing: while the fourth portion of the cycling process was defined, the back portion, that is, the route (mechanism) for the release of Ca²⁺ was not, and was only discovered some years later.

The limited uptake of Ca²⁺ in the absence of phosphate was eventually used to test the proposal of an electrophoretic mechanism for the uptake of Ca²⁺, which would have been consistent with the increasingly popular chemiosmotic principles. Diffusion potentials were artificially imposed across the mitochondrial membrane, showing that Ca²⁺ indeed traversed the membrane in response to an electrochemical gradient. Uncertainties of the various types complicated experiments aimed at establishing whether the mechanism of the uptake process was purely electrophoretic or partially charge compensated, but the presence of an electrophoretic component in the uptake process became generally accepted. As a result, the process of Ca²⁺ transport, which had been initially described as an active uptake followed by a passive release, became an energetically downhill uptake process, followed by an energetically uphill release leg. The uptake leg of the process was postulated to occur on an electrophoretic uniporter, its study being aided greatly by the discovery of specific inhibitors, the most popular being the histochemical stain Ruthenium Red (about 20 years later a derivative, RU360, was introduced, which specifically inhibited the uptake of Ca²⁺ with an IC₅₀ of 0.2–2.0 nM).

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Chemiosmotic and murburn explanations for aerobic respiration: Predictive capabilities, structure-function correlations and chemico-physical logic

Kelath Murali Manoj , ... Nikolai Mikhailovich Bazhin , in Archives of Biochemistry and Biophysics, 2019

8 Further avenues proposed to ratify or demarcate the two models

Several theoretical queries discount the chemiosmosis/rotary ATPsynthase mechanism (as seen in Chapter 6) and quantitative derivations based in murburn concept ratify the DROS-based mechanism (as shown in Chapter 7). Further theoretical explorations and planned experiments as detailed below could potentially ratify the relevance of murburn concept in mOxPhos and differentiate it from the RCPE model.

∗

The multi-molecular Q-Cycle scheme of binding of a molecule each of CoQ, CoQH₂ and Cyt. c to the TM region of Complex III can be reinvestigated through modeling and simulation. Molecular simulations of CoQ (H₂) diffusion in the phospholipid bilayer and binding to various proposed regions of the respiratory complexes should be revisited, owing to clear doubts that had been expressed in the field by renowned workers [50,91]. Similarly, the diffusion of Cyt. c and its binding with Complexes III & IV should be simulated.

∗

The arguments professed herein can be further confirmed by employing- (a) chemical controls and reductionist approach, within controlled-water systems like normal/reverse micelles, with DROS generating/stabilizing systems involving proteins containing Mg/Fe/peroxide/NADH/superoxide/pyrithione-photolysis (as a hydroxyl radical source) and substrate analogs. (b) to demonstrate ATP-synthesis in closed vesicles, proteins can be engineered to incorporate a flavin and a heme cofactor with ADP-binding sites on their surfaces (or an enzyme like cytochrome P450 BM3 may be directionally evolved for ATP synthesis in the lab), in conjunction with a proton-delivering system. (Details for protocols are provided in KMM's original arxiv preprint available at- https://arxiv.org/ftp/arxiv/papers/1703/1703.05827.pdf)

∗

Amphipathic DROS modulating molecules (like vitamin E and fatty acyl vitamin C) and trans-membrane or hydrophobic helices containing redox-active enzymes (like horseradish peroxidase) inhibit membrane-embedded electron transport and redox metabolism in microsomal xenobiotic metabolic (mXM) system [29]. This is when their soluble functional analogs (trolox, ascorbate, and superoxide dismutase) don't inhibit [32] the mXM. Further, many of these inhibitions exhibit a maverick concentration-dependent profile (mM to pM). Such effects of various uncoupling molecules can be further probed and demonstrated in the mOxPhos system. A similar set of reactions could be repeated in a minimalistic model like the Racker's/Otrin's experiments. In conjunction, the inhibitory capacity of retinol, retinal and retinoic acids and their esters could also be compared.

∗

Evolutionary-lineage analysis of respiratory complexes may give evidence of DROS modulation machinery's progression and specific adaptation across domains in various species.

∗

The new paradigm permits the mitochondria to work even without a pH gradient, at low proton concentrations and without high trans-membrane potentials. This projection can be ratified in simple experimental systems [Jagendorf's experiment [5] can be re-done by equilibrating mitochondria at pH 6 and then providing an external buffer of pH 4. The rates obtained above could be compared with an experiment where the mitochondria are equilibrated at pH 8 and then exposed to a buffer at pH 6. Such proton-gradients would be inadequate to power ATP-synthesis [20] per the chemiosmosis hypothesis even from the initialized state. But yet, we may observe a net equilibrium-driven ATP-synthesis, indicating the inapplicability of chemiosmosis hypothesis.].

∗

It can be explored if Complexes III/IV can set a one-electron scheme from CoQH₂ and H₂O₂ in the presence of oxygen + NADH. Further, it can be explored if the respiratory Complexes bind and support ADP-phosphorylation by DROS-chemistry (as duly predicted by murburn scheme).

∗

Cyanide is the most potent cellular respiratory toxin [92] and therefore, it is perhaps the most important tool to investigate the mechanism of mOxPhos. The following exploration and experiments are suggested to further ratify the proposals/deductions of the current work on the impact of cyanide on cellular respiration and toxicity. [[The first three sub-points below have already been ratified through our recent works [45].]]

∗

A comparison could be made between other gaseous and diatomic toxic ligands with cyanide to verify the binding mechanism (in terms of lethal dosage and the physical parameters of ligation), in order to test if cyanide toxicity results due to binding of protein heme centers.

∗

The mechanism of inhibition (relation of IC₅₀ with K_d, Hill Slope, etc.) can also be studied in simpler heme proteins like peroxidases and catalases and the effects thereof can be compared to that of the complex mOxPhos enzyme system like cytochrome oxidase.

∗

In a simple reductionist system, the inhibitory role of cyanide in ATP synthesis can be traced. To a control reaction of ADP + Pi + superoxide, a test reaction of ADP + Pi + superoxide + cyanide can be compared.

∗

In respiring cells or mitochondrial suspension, (sub)micromolar levels of cyanide should be presented and consumption of oxygen and formation of DROS noted. While the binding-based perspective projects cell death and cessation of respiration, the new proposal predicts oxygen consumption leading to DROS formation (albeit at low levels).

∗

The catalytic role of cyanide radical/DROS can be traced by the incorporation of radio-labeled carbon in cyanide or radio-labeled oxygen. After exposing an experimental system to the molecular probes, the radio-labeled cyanate formation can be traced to confirm the radical pathway of CN/oxygen interaction. On the other hand, if CN binding to heme is efficient and irreversible, cyanate should not be formed.

∗

Similarly, if the efficient competitive ligand CO bound that effectively, one should not have DROS production and thereafter, a dissipation reaction of the equation scheme- 2CO + OH* +O ₂ * ^- → HCO ₃ ⁻ + CO ₂ . Confirmation of the radical chemistry can be done with H₂S and CO, by tracing the radio-labeling of C/S and O atom within SO₂/sulfate and CO₂/carbonate, respectively. It is expected that while H₂S would be highly metabolized, CO would be much lesser converted (as it is a better binder and poorer substrate). This could also be because the Hb in the blood would take up significant amounts of CO, and they do not have mitochondria to metabolize via DROS. (This would also explain the evolutionary reason for the higher affinities of Hb for CO, in comparison to Cox.) But per the murburn perspective, a mitochondrial suspension would surely oxidize CO to CO₂ and carbonate. Else, we cannot explain the reversal of toxicity in CO-exposed animals and individuals.

∗

Per the erstwhile purview, since cyanide has no bearing with Complexes I, II, & III (and since the purported ETC works without push or pull), these proteins should assist Complex V to produce ATP via the "proton-based machinery", if the old mechanisms were operative. So, at K_d (mM) concentrations of cyanide taken experimentally [93], only 50% of Complex IV is 'bound by cyanide'. That would still leave 1:1–2:2-3:2-3:4-6:5-9 ratio of the complexes (I:II:III:IV:V:Cyt.c) in the mitochondrial suspension, and only a minimal or stoichiometric loss of activity should be noted. The new scheme predicts an overwhelming loss (practical cessation) in the ATP production ability of the system.

∗

A 'cyanide-blocked' system could be subjected to a favorable external pH gradient (say, 6.5 out to 9.5 in), quite similar to the demonstration by Mitchell's group or a rhodopsin assisted ATP-synthesis via Racker-Stoeckinius type setups [9]. While the erstwhile hypothesis does not seek inhibitions, the new perspective advocates cessation of fresh ATP-synthesis.

∗

In any experimental system above, cyanide could demonstrate a maverick concentration-based modulatory effect. Say, at concentrations near nM levels of cyanide, murburn concept may result in an interesting observation that ATP-synthesis could even be enhanced by a small fraction (say, up to 20%).

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Integral Biomathics 2017: The Necessary Conjunction of Western and Eastern Thought Traditions for Exploring the Nature of Mind and Life

John S. Torday , William B. MillerJr., in Progress in Biophysics and Molecular Biology, 2017

Abstract

Boundary conditions enable cellular life through negentropy, chemiosmosis, and homeostasis as identifiable First Principles of Physiology. Self-referential awareness of status arises from this organized state to sustain homeostatic imperatives. Preferred homeostatic status is dependent upon the appraisal of information and its communication. However, among living entities, sources of information and their dissemination are always imprecise. Consequently, living systems exist within an innate state of ambiguity. It is presented that cellular life and evolutionary development are a self-organizing cellular response to uncertainty in iterative conformity with its basal initiating parameters. Viewing the life circumstance in this manner permits a reasoned unification between Western rational reductionism and Eastern holism.

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Special Issue: The evolving role of mitochondria in metabolism

Ryan J. Mailloux , Mary-Ellen Harper , in Trends in Endocrinology & Metabolism, 2012

Fifty years since Peter Mitchell proposed the theory of chemiosmosis, the transformation of cellular redox potential into ATP synthetic capacity is still a widely recognized function of mitochondria. Mitchell used the term 'proticity' to describe the force and flow of the proton circuit across the inner membrane. When the proton gradient is coupled to ATP synthase activity, the conversion of fuel to ATP is efficient. However, uncoupling proteins (UCPs) can cause proton leaks resulting in poor fuel conversion efficiency, and some UCPs might control mitochondrial reactive oxygen species (ROS) production. Once viewed as toxic metabolic waste, ROS are now implicated in cell signaling and regulation. Here, we discuss the role of mitochondrial proticity in the context of ROS production and signaling.

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