Thiamine deficiency perturbed energy metabolism enzymes in brain mitochondrial fraction of Swiss mice

Abstract

BACKGROUND: Thiamine is an essential cofactor associated with several enzymes in energy metabolism and its deficiency may lead to neurological deficits. Current research evaluated the biochemical and molecular changes in TCA cycle enzymes using the mitochondrial fraction of the brain following thiamine deficiency (TD) in mice.

METHODS: The investigation was carried out on Swiss mice (6-8 week old) allocated into three groups. First group was control; second and third group were made thiamine deficient for 8 and 10 days.

RESULTS: Current study showed that alpha-ketoglutarate dehydrogenase (KGDHC) (thiamine-dependent enzyme) level found to be significantly reduced in experimental groups as compared to control group. In comparison to control group, a significant decrease in the succinate dehydrogenase (SDH) activity was calculated in group II and group III (p<0.0001) mice. Diminished enzymatic activity of fumarase and MDH enzyme in thiamine deficient groups exposed for 8 and 10 days was calculated as compared to control group. The expression analysis of different genes governing TCA cycle enzymes in different experimental groups showed that there was a negotiable change in the expression of fumarase and DLD (dihydrolipoyl dehydrogenase- E3 subunit of KGDHC) whereas a declined in the expression of SDH and two subunits of KGDHC i.e. OGDH (2-oxoglutarate dehydrogenase- E1 subunit of KGDHC) and DLST (dihydrolipoyllysine-residue succinyltransferase- E2 subunit of KGDHC) was observed as compared to control group.

CONCLUSIONS: Hence, current findings strongly entail that TD promotes alteration in energy metabolism in brain mitochondria which will decline the neuronal progression which may lead to neurodegenerative diseases such as Alzheimer’s diseases.

Key words： thiamine; brain; TCA cycle enzymes; mitochondrial dysfunction

Acknowledgments

Authors acknowledge Prof. Aditya Shastri, Vice- Chancellor, Banasthali University Rajasthan for providing the suitable facilities to carry out the present investigation in Department of Bioscience and Biotechnology. Authors are thankful to Indian Council of Medical Research (ICMR), New Delhi for financial support.

Compliance with ethics guidelines

Anupama Sharma received a research grant from ICMR, New Delhi. Anupama Sharma, Renu Bist and Surender Singh declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed in the current study.

References

1 Bist R, Misra  S, Bhatt D K  (2010). Inhibition of lindane-induced toxicity using alpha-lipoic acid and vitamin E in the brain of Mus musculus. Protoplasma, 242(1-4): 49–53

PMID

2 Bogdan A S (1983). Effect of small amounts of 2,4-dichlorophenoxyacetic acid derivatives on thiamine and riboflavin metabolism in the animal body. Vopr Pitan, (2): 59–62 

PMID

3 Bubber P, Ke  Z J, Gibson  G E (2004). Tricarboxylic acid cycle enzymes following thiamine deficiency. Neurochem Int, 45(7): 1021–1028

PMID

4 Capettini L S ,  Cortes S F ,  Gomes M A ,  Silva G A ,  Pesquero J L ,  Lopes M J ,  Teixeira M M ,  Lemos V S  (2008). Neuronal nitric oxide synthase-derived hydrogen peroxide is a major endothelium-dependent relaxing factor. Am J Physiol Heart Circ Physiol, 295(6): H2503–H2511

PMID

5 Dror V, Eliash  S, Rehavi M ,  Assaf Y ,  Biton I E ,  Fattal-Valevski A  (2010). Neurodegeneration in thiamine deficient rats-A longitudinal MRI study. Brain Res, 1308: 176–184

PMID

6 Eliash S, Dror  V, Cohen S ,  Rehavi M  (2009). Neuroprotection by rasagiline in thiamine deficient rats. Brain Res, 1256: 138–148

PMID

7 Gibson G E, Blass  J P (2007). Thiamine-dependent processes and treatment strategies in neurodegeneration. Antioxid Redox Signal, 9(10): 1605–1619

PMID

8 Gibson G E, Hirsch  J A, Cirio  R T, Jordan  B D, Fonzetti  P, Elder J  (2013). Abnormal thiamine-dependent processes in Alzheimer’s Disease. Lessons from diabetes. Mol Cell Neurosci, 55: 17–25

PMID

9 Gibson G E, Ksiezak-Reding  H, Sheu K F ,  Mykytyn V ,  Blass J P  (1984). Correlation of enzymatic, metabolic, and behavioral deficits in thiamin deficiency and its reversal. Neurochem Res, 9(6): 803–814

PMID

10 Gibson G E, Park  L C, Sheu  K F, Blass  J P, Calingasan  N Y (2000). The alpha-ketoglutarate dehydrogenase complex in neurodegeneration. Neurochem Int, 36(2): 97–112

PMID

11 Gibson G E, Sheu  K F, Blass  J P, Baker  A, Carlson K C ,  Harding B ,  Perrino P  (1988). Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch Neurol, 45(8): 836–840

PMID

12 Gibson G E, Starkov  A, Blass J P ,  Ratan R R ,  Beal M F  (2010). Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim Biophys Acta, 1802(1): 122–134

PMID

13 Hill R L, Bradshaw  R A (1969) Fumarase. In: Lowenstein, J.M. (Ed.). Methods Enzymol, 13: 91–92

14 Ke Z J, DeGiorgio  L A, Volpe  B T, Gibson  G E (2003). Reversal of thiamine deficiency-induced neurodegeneration. J Neuropathol Exp Neurol, 62(2): 195–207

PMID

15 Kitto G B (1969) Intra and extra mitochondrial malate dehydrogenases from chicken heart. Methods Enzymol, 13: 106–116

16 Kruse M, Navarro  D, Desjardins P ,  Butterworth R F  (2004). Increased brain endothelial nitric oxide synthase expression in thiamine deficiency: relationship to selective vulnerability. Neurochem Int, 45(1): 49–56

PMID

17 Liu D, Ke  Z, Luo J  (2016) Thiamine deficiency and neurodegeneration: The Interplay among oxidative stress, endoplasmic reticulum stress, autophagy. J Mol Neurobiol, 

18 Lyubarev A E, Kurganov  B I (1989). Supramolecular organization of tricarboxylic acid cycle enzymes. Biosystems, 22(2): 91–102

PMID

19 Mailloux RJ, Beriault  R, Lemire J ,  Singh R ,  Chenier D R  (2007). The tricarboxylic acid cycle, an ancient metabolic network with a novel twist. PLoS One, 8 Suppl e690: 1–10

20 Mergenthaler P, Lindauer  U, Dienel G A ,  Meisel A  (2013). Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci, 36(10): 587–597

PMID

21 Nakano K, Matuda  S, Yamanaka T ,  Tsubouchi H ,  Nakagawa S ,  Titani K ,  Ohta S, Miyata  T (1991). Purification and molecular cloning of succinyltransferase of the rat alpha-ketoglutarate dehydrogenase complex. Absence of a sequence motif of the putative E3 and/or E1 binding site. J Biol Chem, 266(28): 19013–19017

PMID

22 Nose Y, Takahashi  K, Nakamura A  (1976). Thiamine diphosphate-dependent enzyme status due to thiamine deficiency in rat liver. J Nutr Sci Vitaminol (Tokyo), 22(SUPPL): 51–55

PMID

23 Park L C H ,  Zhang H ,  Sheu K F R ,  Calingasan N Y ,  Kristal B S ,  Lindsay J G ,  Gibson G E  (1999). Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia. J Neurochem, 72(5): 1948–1958

PMID

24 Rutter J, Winge  D R, Schiffman  J D (2010). Succinate dehydrogenase- Assembly, regulation and role in human disease. Mitochondrion, 10(4): 393–401

PMID

25 Shaikh A S, Tamloorkar  H L, Yasmeen  R (2012). Malate dehydrogenase activity post exposure recovery from lead intoxicated fresh water fish Anabas testudineus. Int J Biomed Advan Res, 3(Suppl 2): 118–121

26 Sharma A, Bist  R (2014). Thiamine deprivation disturbs cholinergic system and oxidative stress in liver of Mus musculus. Int J Pharm Pharma Sci Sci, 6: 139–143

27 Sharma A, Bist  R, Bubber P  (2013). Thiamine deficiency induces oxidative stress in brain mitochondria of Mus musculus. J Physiol Biochem, 69(3): 539–546

PMID

28 Sheu K F, Calingasan  N Y, Lindsay  J G, Gibson  G E (1998). Immunochemical characterization of the deficiency of the alpha-ketoglutarate dehydrogenase complex in thiamine-deficient rat brain. J Neurochem, 70(3): 1143–1150

PMID

29 Shi Q, Chen  H L, Xu  H, Gibson G E  (2005). Reduction in the E2k subunit of the alpha-ketoglutarate dehydrogenase complex has effects independent of complex activity. J Biol Chem, 280(12): 10888–10896

PMID

33 Singer TP, Kearney  E B, Kenney W C  (1973). Succinate dehydrogenase. Adv Enzymol·Relat Areas Mol Biol, 37: 189–272.

30 Sorbi S, Bird  E D, Blass  J P (1983). Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol, 13(1): 72–78

PMID

31 Tretter L, Adam-Vizi  V (2000). Inhibition of Krebs cycle enzymes by hydrogen peroxide: A key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci, 20(24): 8972–8979

PMID

32 Troncoso J C, Johnston  M V, Hess  K M, Griffin  J W, Price  D L (1981). Model of Wernicke’s encephalopathy. Arch Neurol, 38(6): 350–354

PMID

34 Vélot C, Mixon  M B, Teige  M, Srere P A  (1997). Model of a quinary structure between Krebs TCA cycle enzymes: a model for the metabolon. Biochemistry, 36(47): 14271–14276

PMID

35 Vermulst M, Bielas  J H, Loeb  L A (2008). Quantification of random mutations in the mitochondrial genome. Methods, 46(4): 263–268

PMID

36 Zastre J A, Sweet  R L, Hanberry B S ,  Ye S (2013). Linking vitamin B1 with cancer cell metabolism. Cancer Metabl, 1–16