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Gnaiger 2009 Int J Biochem Cell Biol

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Publications in the MiPMap
Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. https://doi.org/10.1016/j.biocel.2009.03.013

» Int J Biochem Cell Biol 41:1837-45. PMID: 19467914 Bioblast pdf

Gnaiger Erich (2009) Int J Biochem Cell Biol

Abstract:

Fig. 1. Substrate control of electron flow to oxygen through Complex I or Complex II separately (N- or S-pathway), or simultaneously (NS) in mitochondrial preparations. Substrate supply restricted to pyruvate&malate, PM, or succinate&rotenone, S(Rot), exerts artificial upstream control of flux through the linear electron transport chain (ETC). With PM (or GM) as substrates, metabolite depletion (loss of citrate, isocitrate, 2-oxoglutarate and succinate from the matrix) prevents substrate supply to CII. With succinate as the only substrate, blockage of CI is necessary to prevent inhibition of succinate dehydrogenase by accumulating oxaloacetate. Combined NS substrate supply with simultaneous electron entry at the Q-junction exerts an additive effect on total electron flux through the convergent Electron transfer-pathway (ET-pathway). This shifts control of flux downstream towards Complexes III and IV, and towards the phosphorylation system in oxidative phosphorylation. Convergent electron flow corresponds to the operation of the tricarboxylic acid cycle in the intact cell, generating simultaneously NADH and succinate in the matrix as substrates for NS-pathway control. This physiological state is reconsituted in mitochondrial preparations by external NS-substrate supply (PMS; or substituting pyruvate by glutamate, GMS or GS). Substrate entry across the inner mitochondrial membrane into the mitochondrial matrix space is shown by dotted arrows (metabolite depletion from the matrix is not shown). Full arrows indicate flow of electron pairs (single arrows) split into flow of single electrons (double arrows) (after Gnaiger 2009).

Maximal ADP-stimulated mitochondrial respiration depends on NS-convergent electron flow through Complexes I&II to the Q-junction of the electron transport system (ET-pathway). In most studies of respiratory control in mitochondrial preparations, however, respiration is limited artificially by supplying N- or S-substrates for electron input through either Complex I or II. High-resolution respirometry with minimal amounts of tissue biopsy (1 to 3 mg wet weight of permeabilized muscle fibres per assay) provides a routine approach for multiple substrate-uncoupler-inhibitor titrations. Under physiological conditions, maximal respiratory capacity is obtained with glutamate&malate&succinate, reconstituting the operation of the tricarboxylic acid cycle and preventing depletion of key metabolites from the mitochondrial matrix. In human skeletal muscle, conventional assays with pyruvate&malate or glutamate&malate yield submaximal oxygen fluxes at 0.50 to 0.75 of capacity of oxidative phosphorylation (OXPHOS). Best estimates of muscular OXPHOS capacity at 37 °C [pmol O2∙s-1∙mg-1 wet weight] with isolated mitochondria or permeabilized fibres, suggest a range of 100 to 150 and up to 180 in healthy humans with normal body mass index and top endurance athletes, but reduction to 60 to 120 in overweight healthy adults with predominantly sedentary life style. The apparent ET-pathway excess capacity (noncoupled respiration) over ADP-stimulated OXPHOS capacity is high in skeletal muscle of active and sedentary humans, but absent in mouse skeletal muscle. Such differences of mitochondrial quality in skeletal muscle are unexpected and cannot be explained at present. A comparative data base of mitochondrial physiology may provide the key for understanding the functional implications of mitochondrial diversity from mouse to man, and evaluation of altered mitochondrial respiratory control patterns in health and disease.

Keywords: Q-junction, Q-cycle, Pyruvate, Glutamate, Succinate, Tricarboxylic acid cycle

O2k-Network Lab: AT Innsbruck Gnaiger E, AT Innsbruck Oroboros

Abbreviations

  • 2017: For further clarification, NADH-linked respiration (N-respiration; CI-linked) and succinate-linked respiration (S-respiration; CII-linked) are distinguished from combined NS-respiration (CI&II-linked).


Correction

  • Table 2, ref c(1) Ponsot et al. (2005). - The correct reference is Ponsot et al. (2006).
  • Ponsot E, Dufour SP, Zoll J, Doutrelau S, N'Guessan B, Geny B, Hoppeler H, Lampert E, Mettauer B, Ventura-Clapier R, Richard R (2006) Exercise training in normobaric hypoxia in endurance runners. II. Improvement of mitochondrial properties in skeletal muscle. J Appl Physiol (1985) 100:1249-57. - »Bioblast link«

MitoPedia: BME

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MitoPedia: BME

TermAbbreviationDescription
BME cutoff pointsBME cutoffObesity is defined as a disease associated with an excess of body fat with respect to a healthy reference condition. Cutoff points for body mass excess, BME cutoff points, define the critical values for underweight (-0.1 and -0.2), overweight (0.2), and various degrees of obesity (0.4, 0.6, 0.8, and above). BME cutoffs are calibrated by crossover-points of BME with established BMI cutoffs.
Body fat excessBFEIn the healthy reference population (HRP), there is zero body fat excess, BFE, and the fraction of excess body fat in the HRP is expressed - by definition - relative to the reference body mass, M°, at any given height. Importantly, body fat excess, BFE, and body mass excess, BME, are linearly related, which is not the case for the body mass index, BMI.
Body massm [kg]; M [kg·x-1]The body mass M is the mass (kilogram [kg]) of an individual (object) [x] and is expressed in units [kg/x]. Whereas the body weight changes as a function of gravitational force (you are weightless at zero gravity; your floating weight in water is different from your weight in air), your mass is independent of gravitational force, and it is the same in air and water.
Body mass excessBMEThe body mass excess, BME, is an index of obesity and as such BME is a lifestyle metric. The BME is a measure of the extent to which your actual body mass, M [kg/x], deviates from M° [kg/x], which is the reference body mass [kg] per individual [x] without excess body fat in the healthy reference population, HRP. A balanced BME is BME° = 0.0 with a band width of -0.1 towards underweight and +0.2 towards overweight. The BME is linearly related to the body fat excess.
Body mass indexBMIThe body mass index, BMI, is the ratio of body mass to height squared (BMI=M·H-2), recommended by the WHO as a general indicator of underweight (BMI<18.5 kg·m-2), overweight (BMI>25 kg·m-2) and obesity (BMI>30 kg·m-2). Keys et al (1972; see 2014) emphasized that 'the prime criterion must be the relative independence of the index from height'. It is exactly the dependence of the BMI on height - from children to adults, women to men, Caucasians to Asians -, which requires adjustments of BMI-cutoff points. This deficiency is resolved by the body mass excess relative to the healthy reference population.
ComorbidityComorbidities are common in obesogenic lifestyle-induced early aging. These are preventable, non-communicable diseases with strong associations to obesity. In many studies, cause and effect in the sequence of onset of comorbidities remain elusive. Chronic degenerative diseases are commonly obesity-induced. The search for the link between obesity and the etiology of diverse preventable diseases lead to the hypothesis, that mitochondrial dysfunction is the common mechanism, summarized in the term 'mitObesity'.
Healthy reference populationHRPA healthy reference population, HRP, establishes the baseline for the relation between body mass and height in healthy people of zero underweight or overweight, providing a reference for evaluation of deviations towards underweight or overweight and obesity. The WHO Child Growth Standards (WHO-CGS) on height and body mass refer to healthy girls and boys from Brazil, Ghana, India, Norway, Oman and the USA. The Committee on Biological Handbooks compiled data on height and body mass of healthy males from infancy to old age (USA), published before emergence of the fast-food and soft-drink epidemic. Four allometric phases are distinguished with distinct allometric exponents. At heights above 1.26 m/x the allometric exponent is 2.9, equal in women and men, and significantly different from the exponent of 2.0 implicated in the body mass index, BMI [kg/m2].
Height of humansh [m]; H [m·x-1]The height of humans, h, is given in SI units in meters [m]. Humans are countable objects, and the symbol and unit of the number of objects is N [x]. The average height of N objects is, H = h/N [m/x], where h is the heights of all N objects measured on top of each other. Therefore, the height per human has the unit [m·x-1] (compare body mass [kg·x-1]). Without further identifyer, H is considered as the standing height of a human, measured without shoes, hair ornaments and heavy outer garments.
Lengthl [m]Length l is an SI base quantity with SI base unit meter m. Quantities derived from length are area A [m2] and volume V [m3]. Length is an extensive quantity, increasing additively with the number of objects. The term 'height' h is used for length in cases of vertical position (see height of humans). Length of height per object, LUX [m·x-1] is length per unit-entity UX, in contrast to lentgth of a system, which may contain one or many entities, such as the length of a pipeline assembled from a number NX of individual pipes. Length is a quantity linked to direct sensory, practical experience, as reflected in terms related to length: long/short (height: tall/small). Terms such as 'long/short distance' are then used by analogy in the context of the more abstract quantity time (long/short duration).
MitObesity drugsBioactive mitObesity compounds are drugs and nutraceuticals with more or less reproducible beneficial effects in the treatment of diverse preventable degenerative diseases implicated in comorbidities linked to obesity, characterized by common mechanisms of action targeting mitochondria.
ObesityObesity is a disease resulting from excessive accumulation of body fat. In common obesity (non-syndromic obesity) excessive body fat is due to an obesogenic lifestyle with lack of physical exercise ('couch') and caloric surplus of food consumption ('potato'), causing several comorbidities which are characterized as preventable non-communicable diseases. Persistent body fat excess associated with deficits of physical activity induces a weight-lifting effect on increasing muscle mass with decreasing mitochondrial capacity. Body fat excess, therefore, correlates with body mass excess up to a critical stage of obesogenic lifestyle-induced sarcopenia, when loss of muscle mass results in further deterioration of physical performance particularly at older age.
VO2maxVO2max; VO2max/MMaximum oxygen consumption, VO2max, is and index of cardiorespiratory fitness, measured by spiroergometry on human and animal organisms capable of controlled physical exercise performance on a treadmill or cycle ergometer. VO2max is the maximum respiration of an organism, expressed as the volume of O2 at STPD consumed per unit of time per individual object [mL.min-1.x-1]. If normalized per body mass of the individual object, M [kg.x-1], mass specific maximum oxygen consumption, VO2max/M, is expressed in units [mL.min-1.kg-1].

Further references

» MitoPedia: Respiratory states OXPHOS ROUTINE ET-capacity LEAK  - ROX
» O2k-Publications: Human - Skeletal muscle
» O2k-Publications: Q-junction effect

Cited by

Gnaiger 2020 BEC MitoPathways
Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. Bioenerg Commun 2020.2. https://doi.org/10.26124/bec:2020-0002


Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1.
Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1.



Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Exercise physiology;nutrition;life style, mt-Medicine  Pathology: Aging;senescence, Obesity 

Organism: Human, Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue, Isolated mitochondria  Enzyme: Marker enzyme  Regulation: Coupling efficiency;uncoupling  Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS  HRR: Oxygraph-2k, O2k-Protocol 

BMI, BME, Respiratory states, Oxidative phosphorylation, Electron transfer pathway, Uncoupling, LEAK respiration, Flux control ratio, Residual oxygen consumption, Mitochondrial marker, BEC 2020.1, BEC 2020.2, MitoPathways