Succinate dehyrogenase and the Charge Field

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Succinate dehyrogenase and the Charge Field

Post by Cr6 on Wed Aug 12, 2015 1:53 am

May 2002, Volume 10, Number 5, Pages 289-291

Succinate dehydrogenase and human diseases: new insights into a well-known enzyme
Pierre Rustin, Arnold Munnich and Agnès Rötig

Unité de Recherches sur les Handicaps Génétiques de l'Enfant (INSERM U393) Hôpital Necker-Enfants Malades, 149, rue de Sèvres, Paris 75015, France

Correspondence to: P Rustin, Unité de Recherches sur les Handicaps Génétiques de l'Enfant (INSERM U393) Hôpital Necker-Enfants Malades, 149, rue de Sèvres, Paris 75015, France. Tel: +33 1 4449 5161; Fax: +33 1 4734 8514; E-mail:

Inherited defects of the mitochondrial succinate dehydrogenase (SDH) in humans are associated with striking variable clinical presentations ranging from early-onset devastating encephalomyopathy to tumour susceptibility in adulthood, or optic atrophy in the elderly. Although different genes encoding the four subunits of the SDH have been found mutated in association with these different phenotypes, we propose that the wide clinical spectrum actually originates from the specific roles of the SDH in the respiratory chain and the mitochondria. In particular, beside its function in the Krebs cycle and the respiratory chain, the specific redox properties of the enzyme could confer to the SDH a specific function in superoxide handling.


The mitochondrial succinate dehydrogenase (SDH) complex catalyses the oxidation of succinate to fumarate in the Krebs cycle, and feeds electrons to the respiratory chain ubiquinone (UQ) pool1,2 (Figure 1). SDH consists of four nuclearly encoded subunits whose structure and genes being mostly conserved through evolution. In contrast, the other respiratory complexes have gained additional subunits, or conversely can be absent in some organisms, eg complex I in the yeast Saccharomyces cerevisiae. The subunits A and B form the SDH sensu stricto. The other two, subunits C and D, binding a b-type cytochrome, are often referred to as the anchoring subunits, although they are actually required for electron transfer from succinate to the ubiquinone pool as well.

Defects of the succinate dehydrogenase are comparatively rare in human.3 Yet, large differences in clinical presentations have been reported in patients harbouring mutations in one of the four SDH subunit-encoding genes. Mutations in the flavoprotein subunit, SDHA, the very first mutations in a nuclear gene reported to cause a mitochondrial RC defect in mid '90s result in typical mitochondrial encephalopathy, namely Leigh syndrome.4,5 More recently, mutations in subunits B, C and D have been shown to cause paraganglioma, generally benign, vascularised tumours in the head and the neck, or phaeochromocytomas.6,7,8 The carotid body, the most common tumour site, is a highly vascular small organ localised at the bifurcation of the common carotid artery and is a chemoreceptive organ that senses oxygen levels in the blood. Because of the occurrence of somatic mutations of these three genes in tumours, they should be regarded as tumour-suppressor genes.9

So far, SDH is only known to catalyse a unique reaction, which requires the participation of its four subunits, and deleterious mutations in any of the SDH genes should invariably result in a decreased SDH activity. Therefore, the striking phenotypic differences associated with mutations in the four subunits raise puzzling questions. The re-investigation of the long-known properties of the SDH might help to shed light on this problem.

The unique properties of the SDH and its partnership with the ubiquinone pool

Contrasting with most dehydrogenases feeding electrons to the RC, SDH is known to be fully activated upon reduction of the RC and in the presence of ATP, due to dissociation of its physiological inhibitor, oxaloacetate, at the active site.10 As a result, in the presence of ATP, the decreased electron flow from succinate to oxygen is still compatible with a high reduction of the UQ pool. Additionally, UQ concentration in the mitochondrial inner membrane, which is rapidly limiting for most substrate oxidation upon UQ extraction, is only poorly limiting for succinate oxidation.11 This suggests that the SDH might 'see' (requires less) UQ when other dehydrogenases do not. In keeping with this, oxygen uptake measured with isolated mitochondria in the presence of a combination of NADH and succinate is less than the sum of the individual rates, mainly because of the reduction of the electron flow from the NADH dehydrogenase.12 This again indicated the successful competition of the SDH to reduce the UQ pool. The powerful reducing activity of the SDH is also illustrated by its distinctive ability to possibly trigger reverse electron flow through the respiratory chain complex I, ultimately resulting in NADH production. Reverse electron flow from succinate to NADH has been reported in higher plants and mammalian cells.13,14,15 All these observations support the view that SDH plays a specific role in the maintenance of the mitochondrial UQ pool reduction.

Ubiquinone, beside its function in the RC as an electron carrier mediating electron transfer between the various dehydrogenases and the cytochrome path, is admittedly working as a powerful antioxidant in biological membranes.16 Possibly for this exact reason, it is in much larger amounts compared to other electron carriers of the RC,1 including the sum of the dehydrogenases. Then, only a portion of the UQ pool may be actually involved in electron transfer depending on dehydrogenases involved. Accordingly, the measurable redox status of the UQ pool should result from the reducing activity of the different dehydrogenases, the oxidising activity of complex III and the kinetic equilibrium in the pool. The UQ pool therefore represents an electron sink and, when reduced, an antioxidant reservoir in the mitochondrial inner membrane. However, UQ is a double-faced compound, possibly working as either an anti-oxidant when fully reduced to ubiquinol, or a pro-oxidant when semi-reduced to the unstable ubisemiquinone form.16 Possibly together with reduced cytochrome b, semi-reduced quinones constitute the prominent source of superoxides by the RC under state 4 conditions.1 Finally, when defective, the RC can produce an abnormal amount of superoxides involving additional RC components, eg flavin radicals of complex I.17 Delivering electrons for the full reduction of UQ to UQH2 might then be of a tremendous importance for the control of oxygen toxicity in the mitochondria. Therefore, the SDH, thanks to its unique redox properties, may be a key enzyme to control UQ pool redox poise under these conditions.

SDH deficiencies: reduced electron flow and/or increased oxygen toxicity

It is noticeable that inherited deficiencies of SDH associated with SDHA mutations are always associated with relatively high residual activities, ranging from 25-50% of control mean values.4,5 As a comparison, less than 5% residual activity is frequently measured in patients with severe defect of complex IV or I. However, patients with such SDH defect present typical Leigh syndrome and thus do not clinically differ from patients with other RC complex defects.18 Interestingly enough, a late-onset optic atrophy has also been ascribed to a heterozygous mutation in SDHA in two patients with 50% residual SDH activity.19 In none of these cases was the presence of tumour reported.

Contrasting with the high residual activity measured in patients with mutations in the SDHA gene, SDH activity is barely detectable in tumour tissues from patients with hereditary paraganglioma.20 The total lack of activity predictably originates from the highly deleterious mutations identified in the only allele expressed in the tumour. As discussed above, the lack of SDH activity will not only cause decreased ATP production-a condition that results from severe CI or CIV defect as well-but will also deprive the RC of the only dehydrogenase activity able to maintain a high reduction status of the UQ pool. This may in turn cause the loss of the anti-oxidant capacity of the respiratory chain and possibly an oxidative stress that is known to readily trigger tumour formation.

Oxygen and SDH: worms as well

Observations made with the worm Caenorhabditis elegans also support the idea that the SDH plays a specific role in the handling of oxygen by mitochondria. Strangely enough, a specific SDH mutation-rather than a whole class of respiratory chain mutants-was identified in an oxygen-hypersensitivite worm.21 Tumour formation has not been described in C. elegans, but the mutant worm shows a shortened life span. In humans, mutations in any of the SDH cause the complex II to fully disassemble. Then, being absent, complex II can be disregarded as a source of additional superoxide production. Thus, we propose that the superoxide overproduction, admittedly leading to tumour formation in human and hypersensitivity to oxygen in the mutant worm, should be ascribed to the decreased ability of the SDH to adequately reduce the UQ pool, a necessary condition to resist oxidative stress.

Studying SDH-related human diseases therefore suggests that the enzyme not only plays a central role in the Krebs cycle and the respiratory chain, but also differs from other mitochondrial dehydrogenases thanks to its unique redox properties. In partnership with ubiquinone, SDH would represent a crucial antioxidant enzyme in the mitochondria controlling superoxides scavenging activity of the RC. It is therefore perhaps not so surprising that a wide spectrum of human diseases echoes the mutations in this multi-functional enzyme.

1 Tzagoloff A. Mitochondria New York, Plenum Press, 1982, pp 1-342.

2 Ackrell BAC, Johnson MK, Gunsalus RP, Cecchini G. Structure and function of succinate dehydrogenase and fumarate reductase. in Muller F (ed) Chemistry and Biochemistry of Flavoproteins Boca Raton, FL: CRC Press, 1992, vol III, pp 229-297.

3 Rustin P, Rötig A. Inborn errors of complex II-Unusual human mitochondrial diseases. Biochim Biophys Acta 2001; 1553: 117-122.

4 Bourgeron T, Rustin P, Chretien D et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genet 1995; 11: 144-149. MEDLINE

5 Parfait B, Chretien D, Rötig A, Marsac C, Munnich A, Rustin P. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet 2000; 106: 236-243. Article MEDLINE

6 Baysal BE, Ferrell RE, Willett-Brozick JE et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000; 287: 848-851. Article MEDLINE

7 Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genet 2000; 26: 268-270. Article MEDLINE

8 Astuti D, Latif F, Dallol A et al. Gene mutations in the succinate dehydrogenase subunit sdhb cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001; 69: 49-54. MEDLINE

9 Baysal BE, Rubinstein WS, Taschner PE. Phenotypic dichotomy in mitochondrial complex II genetic disorders. J Mol Med 2001; 79: 495-503. MEDLINE

10 Gutman M. Modulation of mitochondrial succinate dehydrogenase activity, mechanism and function. Mol Cell Biochem 1978; 20: 41-60. MEDLINE

11 Geromel V, Kadhom N, Ceballos-Picot I et al. Human cultured skin fibroblasts survive profound inherited ubiquinone depletion. Free Rad Res 2001; 35: 11-21.

12 Geromel V, Parfait B, von Kleist-Retzow JC et al. The consequences of a mild respiratory chain deficiency on substrate competitive oxidation in human mitochondria. Biochem Biophys Res Commun 1997; 236: 643-646. Article MEDLINE

13 Rustin P, Lance C. Succinate-driven reverse electron transport in the respiratory chain of plant mitochondria. The effects of rotenone and adenylates in relation to malate and oxaloacetate metabolism. Biochem J 1991; 274: 249-255. MEDLINE

14 Eaton S, Turnbull DM, Bartlett K. Redox control of beta-oxidation in rat liver mitochondria. Eur J Biochem 1994; 220: 671-681. MEDLINE

15 Rustin P, Parfait B, Chretien D et al. Fluxes of nicotinamide adenine dinucleotides through mitochondrial membranes in human cultured cells. J Biol Chem 1996; 271: 14785-14790. MEDLINE

16 Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta 1995; 1271: 195-204. MEDLINE

17 Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 2000; 25: 502-508. MEDLINE

18 Munnich A, Rustin P. Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet 2001; 106: 4-17. Article MEDLINE

19 Birch-Machin MA, Taylor RW, Cochran B, Ackrell BA, Turnbull DM. Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol 2000; 48: 330-335. MEDLINE

20 Gimenez-Roqueplo AP, Favier J, Rustin P et al. The R22X mutation of the SDHD gene hereditary paraganglioma suppresses enzymatic activity of complex II in mitochondrial respiratory chain and induces activation of hypoxia pathway. Am J Hum Genet 2001; 69: 1186-1197. MEDLINE

21 Ishii N, Fujii M, Hartman PS et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 1998; 394: 694-697. Article MEDLINE

Figure 1 The several functions of the succinate dehydrogenase in the mitochondria. The succinate dehydrogenase catalyses the oxidation of succinate into fumarate in the Krebs cycle (1), derived electrons being fed to the respiratory chain complex III to reduce oxygen and form water (2). This builds up an electrochemical gradient across the mitochondrial inner membrane allowing for the synthesis of ATP. Alternatively, electrons can be diverted to reduce the ubiquinone pool (UQ pool) and provide reducing equivalents necessary to reduce superoxide anions originating either from an exogenous source or from the respiratory chain itself (3). A complete lack of succinate dehydrogenase activity will hamper electron flow to both respiratory chain complex III and the quinone pool, resulting in a major oxidative stress known to promote tumor formation in human. UQ: ubiquinone; CI, CIII, CIV: the various complexes of the respiratory chain.


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Re: Succinate dehyrogenase and the Charge Field

Post by Cr6 on Wed Aug 12, 2015 1:56 am

Here's an interesting take on Malonic Acid (and Malic Acid) and Cancer:

Malonic Acid

Is an industrial chemical. It is found in sprayed food, dentalware, water, cookware, dishes, utensils.

It also has an internal source. Tapeworm larvae and other parasites such as fasciolopsis buski, fasciola hepatica and paragonimus infect our tissues, releasing malonic and maleic acids.

Malonic acid is very damaging especially in cancer and other degenerative diseases because it interferes with respiration (the making of ATP in mitochondria). When our cells are accidentally fed t malonic acid, they mistake it for succinic acid because the molecules are "look-alikes." The Krebs cycle stalls. And because every step is dependent on the previous step the entire chain of metabolism, called respiration, stalls. It was known by 1909 that malonic acid is a severe respiratory inhibitor.

Maleic acid, part of the "M" family (malonic family) causes effusates which are seepages of body fluid into places where it does not belong. This "water accumulation" can take place in lung, abdomen or other other less common sites.

Methyl malonate is a serious kidney toxin and causes kidney failure. Removing it improves kidney function.

Scientists studied malonic acid, also called malonate, intensely for decades though never suspecting its true significance for humans. A lengthy and excellent review of malonate research has been published in Enzyme And Metabolic Inhibitors Vol. II (see previous footnote). Here is a partial list of topics reviewed.

   Malonate inhibits uptake of glycine and alanine.
   Malonate may chelate iron so it can’t be incorporated into hemoglobin.
   Malonate inhibits healing.
   Motility of sperm is reduced by malonate.
   Bacterial phagocytosis by human neutrophils is depressed by malonate.
   Malonate chelates calcium.
   Malonate drops the resting potential of muscle.
   Malonate causes air hunger (dyspnea).
   Methyl malonate is toxic to the kidney.
   Acetoacetyl Co A can transfer its Co A to malonic acid to make malonyl Co A. This could lead to acetoacetate buildup, namely ketonuria and possibly a block in fat utilization of even numbered carbon atoms, leaving odd numbered carbons to predominate.
   Malonic acid reacts with aldehydes.
   Thallium is chelated by malonic acid into a stable compound. (This could explain accumulation effect in a tumor.)
   A color test for malonates is tetra hydroquinoline-N-propinal to form blue-violet compounds. It is sensitive to 0.01 mg malonate.
   Malonate complexes with zinc and magnesium.
   A fall in malate concentration due to malonate causes depletion of NADP.
   Malonate induces ketonemia.
   Malonate reduces oxygen uptake. Coenzyme Q10 is required to make ATP.
   Malonate raises cholesterol.
   D-malic acid complexes with malic dehydrogenase and NADH, but is enzymatically inactive.
   Maleic acid is competitive inhibitor of succinic dehydrogenase.
   Synergism between rotenone and malonate occurs in mitochondria.
   Malonate causes oxidation of NADH and cytochromes.
   Rats can convert malonate to acetate in the presence of malonyl Co A.
   Malonate reduces survival of infected animals.
   Malonate fed to dogs is recovered as methyl malonate in urine.
   Malonate can pick up an amino group from glutamine.
   Hemolysis of red blood cells may be caused by malonyl dialdehyde (MDA), a derivative of malonic acid.
   Malonate catalyses renal glutaminase; with less glutamine uric acid levels fall.
   Malic acid (apple juice) is the best antidote to malonic acid. (But commercial sources contain patulin which depletes cellular glutathione.)
   Malonic acid is present in urine.
   Malonate depresses the reduction of GSSG to glutathione.
   Malonate inhibits protoporphyrin formation 32%.
   Malonate inhibits insulin stimulation of muscle respiration.
   Malonate inhibits acetylcholine synthesis.
   Mycobacterium phlei respiration is stimulated by malonate. (All schizophrenia cases I see test positive to this bacterium in the brain!)
   Malonate is put into soy sauce in Japan.
   Malonate stimulates Entamoeba histolytica growth.
   Malonate inhibits phosphate entry into cells.
   Potassium transport into cells is inhibited by malonate.
   Malonate causes systemic acidosis.
   Calcium and iron transport by rat duodenum is severely reduced by malonate.
   Malonate inhibits pyruvate oxidation.
   Malonate causes increased utilization of glucose due to the Pasteur effect of a blocked Krebs cycle.
   Lactic acid formation is increased with malonate inhibition of respiration.
   Glycolysis is stimulated by malonate.
   Malonate has different effects on different tissues.
   Much less glucose goes to form amino acids and proteins in the presence of malonate.
   Malonate induces the appearance of the pentose phosphate shunt.
   Malonate diverts fatty acid metabolism to acetoacetate.
   Malonate increases the formation of fatty acids up to 10-fold.
   Maleic acid is a potent inhibitor of urinary acidification.
   Malonate inhibits oxidation of fatty acids.
   Malonate fed to dogs produces acetoacetate, acetone and alcohol.
   Malonate can reduce the concentration of magnesium and calcium to 25% or 50%.
   The methyl derivative of malonate depresses renal function.
   Malonic acid can form malonyl coenzyme A, which is very stable, thereby depleting the system of coenzyme A.
   (Coenzyme A has a nucleic acid base, adenine, plus pantothenic acid and sulfur in its makeup. You will have an increased need for these nutrients.)
   Malonate inhibits urea formation by reducing the supply of oxaloacetate.
   Malonate inhibits cell cleavage (the formation of a wall between 2 dividing cells).
   Benzaldehyde reacts with malonic acid.

The body detoxifies Malonic acid in this way:



   Drink parsley water boiled 5 minutes, 2 cups in divided doses daily
   Vitamin B12 - 6 mg
   Folic acid - 25 mg
   Increase Vitamin C (or rosehips) to double amounts


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