MitoPedia: Respiratory control ratios

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MitoPedia: Respiratory control ratios

MitoPedia - high-resolution terminology - matching measurements at high-resolution.
The MitoPedia terminology is developed continuously in the spirit of Gentle Science.


MitoPedia - high-resolution terminology - matching measurements at high-resolution (n.a. = no abbreviation).
» O2k-Publications: Coupling efficiency;uncoupling
» Flux control
See also
» MitoPedia: Respiratory states
» MitoPedia: SUIT
» Respirometry
»Cell ergometry
TermAbbreviationDescription
Biochemical coupling efficiencyjE-LE-L coupling efficiency The biochemical coupling efficiency is the E-L coupling efficiency, (E-L)/E = 1-L/E. This is equivalent to the P-L control efficiency, (P-L)/P = 1-L/P, only at zero E-P excess capacity, when P = E). The biochemical coupling efficiency is independent of kinetic control by the phosphorylation system.
CI control ratioN/NS; CI/CI&IISee N/NS pathway control ratio
CII control ratioS/NS; CII/CI&IISee S/NS pathway control ratio
Coupling-control efficiencyCoupling-control efficiencies are flux control efficiencies jZ-Y at a constant ET-pathway competent state.
Coupling-control ratioCCRCoupling-control ratios CCR are flux control ratios FCR at a constant mitochondrial pathway-control state. In mitochondrial preparations, there are three well-defined coupling states of respiration: LEAK respiration, OXPHOS, and Electron-transfer-pathway state (ET state). In these states, the corresponding respirtory rates are symbolized as L, P, and E. In living cells, the OXPHOS state cannot be induced, but in the ROUTINE state the respiration rate is R. A reference rate Z is defined by taking Z as the maximum flux, i.e. flux E in the ET-state, such that the lower and upper limits of the CCR are defined as 0.0 and 1.0. Then there are two mitochondrial CCR, L/E and P/E, and two CCR for living cells, L/E and R/E.
Cytochrome c control efficiencyjcThe cytochrome c control efficiency expresses the control of respiration by externally added cytochrome c, c, as a fractional change of flux from substrate state CHNO to CHNOc. In this flux control efficiency, CHNOc is the reference state with stimulated flux; CHNO is the background state with CHNO substrates, upon which c is added:
jc = (JCHNOc-JCHNO)/JCHNOc.
» MiPNet article
E-L coupling efficiencyjE-LE-L coupling efficiency The E-L coupling efficiency, jE-L = (E-L)/E = 1-L/E, is 0.0 at zero coupling (L=E) and 1.0 at the limit of a fully coupled system (L=0). The background state is the LEAK state which is stimulated to flux in the electron transfer pathway reference state by uncoupler titration. LEAK states LN or LT may be stimulated first by saturating ADP (rate P in the OXPHOS state) with subsequent uncoupler titration to the ET state with maximum rate E. The E-L coupling efficiency is based on measurement of a coupling-control ratio (LEAK-control ratio, L/E), whereas the thermodynamic or ergodynamic efficiency of coupling between ATP production (phosphorylation of ADP to ATP) and oxygen consumption is based on measurement of the output/input flux ratio (P»/O2 ratio) and output/input force ratio (Gibbs force of phosphorylation/Gibbs force of oxidation). The biochemical coupling efficiency expressed as the E-L coupling efficiency is independent of kinetic control by the E-P control efficiency, and is equal to the P-L control efficiency if P=E as evaluated in a coupling-control protocol. » MiPNet article
E-P control efficiencyjE-PE-P control efficiency The E-P control efficiency, jE-P = (E-P)/E = 1-P/E, is an expression of the relative limitation of OXPHOS capacity by the capacity of the phosphorylation system. It is the normalized E-P excess capacity. jE-P = 0.0 when OXPHOS capacity is not limited by the phosphorylation system at zero E-P excess capacity, P=E, when the phosphorylation system does not exert any control over OXPHOS capacity. jE-P increases with increasing control of the phosphorylation system over OXPHOS capacity. jE-P = 1 at the limit of zero phosphorylation capacity. The OXPHOS state of mt-preparations is stimulated to electron transfer pathway capacity E by uncoupler titration, which yields the E-P excess capacity.
E-R control efficiencyjE-RE-R control efficiency The E-R control efficiency, jE-R = (E-R)/E = 1-R/E, is an expression of the relative scope of increasing ROUTINE respiration in living cells by uncoupling. jE-R = 0.0 for zero E-R reserve capacity when R=E; jE-R = 1.0 for the maximum limit when R=0. The ROUTINE state of living cells is stimulated to electron transfer pathway capacity by uncoupler titration, which yields the E-R reserve capacity. Since ET capacity is significantly higher than OXPHOS capacity in various cell types (as shown by cell ergometry), jE-R is not a reserve capacity available for the cell to increase oxidative phosphorylation, but strictly a scope (reserve) for uncoupling respiration. Similarly, the apparent E-P excess ET capacity is not a respiratory reserve in the sense of oxidative phosphorylation.
Ergodynamic efficiencyεThe ergodynamic efficiency, ε (compare thermodynamic efficiency), is a power ratio between the output power and the (negative) input power of an energetically coupled process. Since power [W] is the product of a flow and the conjugated thermodynamic force, the ergodynamic efficiency is the product of an output/input flow ratio and the corresponding force ratio. The efficiency is 0.0 in a fully uncoupled system (zero output flow) or at level flow (zero output force). The maximum efficiency of 1.0 can be reached only in a fully (mechanistically) coupled system at the limit of zero flow at ergodynamic equilibrium. The ergodynamic efficiency of coupling between ATP production (DT phosphorylation) and oxygen consumption is the flux ratio of DT phosphorylation flux and oxygen flux (P»/O2 ratio) multiplied by the corresponding force ratio. Compare with the OXPHOS-coupling efficiency.
Flux control efficiencyjZ-YFlux control efficiencies express the control of respiration by a metabolic control variable, X, as a fractional change of flux from YX to ZX, normalized for ZX. ZX is the reference state with high (stimulated or un-inhibited) flux; YX is the background state at low flux, upon which X acts.
jZ-Y = (ZX-YX)/ZX = 1-YX/ZX

Complementary to the concept of flux control ratios and analogous to elasticities of metabolic control analysis, the flux control efficiency of X upon background YX is expressed as the change of flux from YX to ZX normalized for the reference state ZX.

» MiPNet article
Flux control ratioFCRFlux control ratios FCR are ratios of oxygen flux in different respiratory control states, normalized for maximum flux in a common reference state, to obtain theoretical lower and upper limits of 0.0 and 1.0 (0 % and 100 %). For a given protocol or set of respiratory protocols, flux control ratios provide a fingerprint of coupling and substrate control independent of (1) mt-content in cells or tissues, (2) purification in preparations of isolated mitochondria, and (3) assay conditions for determination of tissue mass or mt-markers external to a respiratory protocol (CS, protein, stereology, etc.). FCR obtained from a single respirometric incubation with sequential titrations (sequential protocol; SUIT protocol) provide an internal normalization, expressing respiratory control independent of mitochondrial content and thus independent of a marker for mitochondrial amount. FCR obtained from separate (parallel) protocols depend on equal distribution of subsamples obtained from a homogenous mt-preparation or determination of a common mitochondrial marker.
HyphenationHyphenation is used to connect two words (compound words) or two parts of a word to clarify the meaning of a sentence. The same two words may be hyphenated or not depending on context. Hyphenation may present a problem when searching for a term such as 'Steady state'. It is helpful to write 'steady-state measurement', to clarify that the measurement is performed at steady state, rather than implying that a state measurement is steady. But this does not imply that hyphenation is applied to the 'measurement performed at steady state'. Thus, the key word is 'steady state'. Compound adjectives should be hyphenated (steady-state measurement), but if the compound adjective follows the term (measurement at steady state), hyphenation does not add any information and should be avoided. Find more examples and guidelines in the grammarly blog on Hyphen and in apastyle.apa.org.
L/E coupling-control ratioL/ELEAK control ratio The L/E coupling-control ratio is the flux ratio of LEAK respiration over ET capacity, as determined by measurement of oxygen consumption in L and E sequentially. The L/E coupling-control ratio is an index of uncoupling or dyscoupling at constant ET-capacity. L/E increases with uncoupling from a theoretical minimum of 0.0 for a fully coupled system, to 1.0 for a fully uncoupled system.
L/P coupling-control ratioL/PL/P coupling-control ratio The L/P coupling-control ratio or LEAK/OXPHOS coupling-control ratio combines the effects of coupling (L/E) and limitation by the phosphorylation system (P/E); L/P = (L/E) / (P/E) = 1/RCR.
L/R coupling-control ratioL/RL/R coupling-control ratio The L/R coupling-control ratio or LEAK/ROUTINE coupling-control ratio combines the effects of coupling (L/E), physiological control of energy demand, and limitation by the OXPHOS capacity.
Metabolic control variableXA metabolic control variable X causes the transition between a background state Y (background rate YX) and a reference state Z (reference rate ZX). X may be a stimulator or activator of flux, inducing the step change from background to reference steady state (Y to Z). Alternatively, X may be an inhibitor of flux, absent in the reference state but present in the background state (step change from Z to Y).
N/NS pathway control ratioN/NSThe N/NS pathway control ratio is obtained when succinate is added to N-linked respiration in a defined coupling state. N and NS are abbreviations for respiration in the N-pathway control state (with pyruvate, glutamate, malate, or other ETS competent N-linked substrate combinations) and the NS-pathway control state (N in combination with succinate). NS indicates respiration with a cocktail of substrates supporting the N- and S-pathways.
N/S pathway control ratioN/SThe N/S pathway control ratio is obtained from SUIT protocols when the N-pathway flux and S-pathway flux are measured in the same coupling control state. The N/S pathway control ratio may be larger or smaller than 1.0, depending on the mitochondrial source and various mitochondrial injuries. The S-pathway control state may be selected preferentially as reference state, if mitochondria are studied with respect to N-pathway injuries.
NS-N pathway control efficiencyjNS-N; jCI&II-CIThe NS-N pathway control efficiency, jNS-N = 1-N/NS, expresses the fractional change of flux when succinate is added to the N-pathway control state in a defined coupling-control state.
NS-S pathway control efficiencyjNS-SThe NS-S pathway control efficiency expresses the relative stimulation of succinate supported respiration (S) by NADH-linked substrates (N), with the S-pathway control state as the background state and the NS-pathway control state as the reference state. In typical SUIT protocols with type N and S substrates, flux in the NS-pathway control state NS is inhibited by rotenone to measure flux in the S-pathway control state, S(Rot) or S. Then the NS-S pathway control efficiency in the ET-coupling state is
j(NS-S)E = (NSE-SE)/NSE
The NS-S pathway control efficiency expresses the fractional change of flux in a defined coupling-control state when inhibition by rotenone is removed from flux under S-pathway control in the presence of a type N substrate combination. Experimentally rotenone Rot is added to the NS-state. The reversed protocol, adding N-substrates to a S-pathway control background does not provide a valid estimation of S-respiration with succinate in the absence of Rot, since oxaloacetate accumulates as a potent inhibitor of succinate dehydrogenase CII.
Net P/E control ratio(P-L)/Enet P/E control ratio The net P/E control ratio, (P-L)/E, expresses the OXPHOS capacity (corrected for LEAK respiration) as a fraction of ET capacity. The net P/E control ratio remains constant, if dyscoupling is fully compensated by an increase of OXPHOS capacity and net OXPHOS capacity P-L, P-L, is maintained constant.
Net R/E control ratio(R-L)/Enet R/E control ratio The net R/E control ratio, (R-L)/E, expresses phosphorylation-related respiration (corrected for LEAK respiration) as a fraction of ET capacity. The net R/E control ratio remains constant, if dyscoupling is fully compensated by an increase of ROUTINE respiration and R-L net ROUTINE capacity, R-L, is maintained constant.
Normalization of rateNormalization of rate (respiratory rate, rate of hydrogen peroxide production, growth rate) is required to report experimental data. Normalization of rates leads to a diversity of formats. Normalization is guided by physicochemical principles, methodological considerations, and conceptual strategies. The challenges of measuring respiratory rate are matched by those of normalization. Normalization of rates for: (1) the number of objects (cells, organisms); (2) the volume or mass of the experimental sample; and (3) the concentration of mitochondrial markers in the instrumental chamber are sample-specific normalizations, which are distinguished from system-specific normalization for the volume of the instrumental chamber (the measuring system). Metabolic flow, I, per countable object increases as the size of the object is increased. This confounding factor is eliminated by expressing rate as sample-mass specific or sample-volume specific flux, J. Flow is an extensive quantity, whereas flux is a specific quantity. If the aim is to find differences in mitochondrial function independent of mitochondrial density, then normalization to a mitochondrial marker is imperative. Flux control ratios and flux control efficiencies are based on internal normalization for rate in a reference state, are independent of externally measured markers and, therefore, are statistically robust.
P-L control efficiencyjP-LP-L control efficiency The P-L control efficiency (P-L flux control efficiency) is defined as jP-L = (P-L)/P = 1-L/P. OXPHOS capacity corrected for LEAK respiration is the P-L net OXPHOS capacity, P-L. The P-L control efficiency is the ratio of net to total OXPHOS capacity, which is equal to the biochemical E-L coupling efficiency, if P=E. jP-L = 1.0 for a fully coupled system (when RCR approaches infinity); jP-L = 0.0 (RCR=1) for a system with zero respiratory phosphorylation capacity (P-L=0) or zero E-L coupling efficiency (E-L=0 when L=P=E). If State 3 is measured at saturating concentrations of ADP and Pi (State 3 = P), then the respiratory acceptor control ratio RCR equals P/L. Under these conditions, the respiratory control ratio and P-L control efficiency are related by a hyperbolic function, jP-L = 1-RCR-1. » MiPNet article
P/E control ratioP/EOXPHOS-control ratio The P/E control ratio (OXPHOS/ET pathway; phosphorylation system control ratio) is an expression of the limitation of OXPHOS capacity by the phosphorylation system. The relative limitation of OXPHOS capacity by the capacity of the phosphorylation system is better expressed by the E-P control efficiency, jE-P = 1-P/E. The P/E control ratio increases with increasing capacity of the phosphorylation system up to a maximum of 1.0 when it matches or is in excess of ET capacity. P/E also increases with uncoupling. P/E increases from the lower boundary set by L/E (zero capacity of the phosphorylation system), to the upper limit of 1.0, when there is no limitation of P by the phosphorylation system or the proton backpressure (capacity of the phosphorylation system fully matches the ET capacity; or if the system is fully uncoupled). It is important to separate the kinetic effect of ADP limitation from limitation by enzymatic capacity at saturating ADP concentration. » MiPNet article
Pathway control efficiencyjZ-YPathway control efficiencies are flux control efficiencies, expressing the relative change of flux in response to a transition between two electron-transfer-pathway states due to a change of (1) substrate availability or (2) inhibition of enzyme steps in the pathway, in a defined coupling-control state.
Pathway control ratioFCRSubstrate control ratios are flux control ratios FCR, at a constant mitochondrial coupling-control state. Whereas there are only three well-defined coupling-control states of mitochondrial respiration, L, P, E (LEAK respiration, OXPHOS, Electron transfer pathway), numerous Electron-transfer-pathway states are possible. Careful selection of the reference state, Jref, is required, for which some guidelines may be provided without the possibility to formulate general rules. FCR are best defined by taking Jref as the maximum flux (e.g. NSE), such that flux in various other respiratory states, Ji, is smaller or equal to Jref. However, this is not generally possible with FCR. For instance, the N/S pathway control ratio (at constant coupling-control state) may be larger or smaller than 1.0, depending on the mitochondrial source and various mitochondrial injuries. The S-pathway control state may be selected preferentially as Jref, if mitochondria with variable N-linked injuries are studied. In contrast, the reference state, Z, is strictly defined for flux control efficiency.
R-L control efficiencyjR-LR-L ROUTINE-coupling efficiency The R-L control efficiency, jR-L = (R-L)/R = 1-L/R, is the fraction of ROUTINE respiration coupled to phosphorylation in living cells. ROUTINE respiration is corrected for LEAK respiration to obtain the R-L net ROUTINE capacity. The flux control efficiency jR-L is the R-L net ROUTINE capacity normalized for the reference rate R. The background state is the LEAK state, and the flux control variable is stimulation to ROUTINE respiration by physiologically controlled ATP turnover in living cells.
R/E control ratioR/ER/E control ratio The R/E control ratio is the ratio of (partially coupled) ROUTINE respiration R and (noncoupled) ET capacity E. The R/E control ratio is an expression of how close ROUTINE respiration operates to ET capacity.
Respiratory acceptor control ratioRCRThe respiratory acceptor control ratio (RCR) is defined as State 3/State 4 [1]. If State 3 is measured at saturating [ADP], RCR is the inverse of the OXPHOS control ratio, L/P (when State 3 is equivalent to the OXPHOS state, P). RCR is directly but non-linearly related to the OXPHOS-coupling efficiency, j≈P = 1-L/P. Whereas the normalized flux ratio j≈P has boundaries from 0.0 to 1.0, RCR ranges from 1.0 to infinity, which needs to be considered when performing statistical analyses. In intact cells, the term RCR has been used for the ratio State 3u/State 4o, i.e. for the inverse L/E ratio [2,3]. Then for conceptual and statistical reasons, RCR should be replaced by the E-L coupling efficiency, j≈E= 1-L/E [4].
S/NS pathway control ratioS/NSThe S/NS pathway control ratio is obtained when rotenone (Rot) is added to the NS-pathway control state in a defined coupling control state. The reversed protocol, adding N-type substrates to a S-pathway control state as the background state does not provide a valid estimation of S-linked respiration with succinate in the absence of Rot, since oxaloacetate accumulates as a potent inhibitor of succinate dehydrogenase (CII).
Substrate control efficiencySee Pathway control efficiency
Substrate control ratioSee Pathway control ratio
Uncoupling-control ratioUCRThe uncoupling-control ratio UCR is the ratio of ET-pathway/ROUTINE-respiration (E/R) in living cells, evaluated by careful uncoupler titrations (Steinlechner et al 1996). Compare ROUTINE-control ratio (R/E) (Gnaiger 2008).
Flux control ratios related to coupling in mt-preparations and living cells: L/P coupling control ratio L/R coupling control ratio LEAK-control ratio OXPHO-control ratio ROUTINE-control ratio
Net respiratory control ratios: netOXPHOS control ratio netROUTINE control ratio
Coupling control factors for free and excess capacities: OXPHOS-coupling efficiency ROUTINE coupling efficiency E-L coupling efficiency Excess E-P capacity factor Excess E-R capacity factor