Tanaka 2017 MiPschool Obergurgl

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Metabolomic analysis of the effect of heavy water on mitochondrial oxidative phosphorylation.

Link: MitoEAGLE

Tanaka M, Iketani M, Ohsawa I, Kami K, Kojima T, Fujita Y, Ito M (2017)

Event: MiPschool Obergurgl 2017

COST Action MitoEAGLE

Mitochondrial diseases are classified into intractable disorders, which require special attention for development of novel therapeutics and diagnostics. Toward this goal, we proposed sodium pyruvate therapy for mitochondrial diseases [1] and we developed in vitro diagnosis system with serum GDF15 for this disorder [2,3].

In parallel with these translational studies, we conducted our basic studies on the pathomechanisms of mitochondrial dysfunction. Stable isotopes, especially 13C, are a useful tool to identify metabolomic changes in cybrid cells carrying the m.3243A>G mutation. We have demonstrated that mitochondrial dysfunction of these cells can be meliorated with sodium pyruvate [4]. We have also utilized 13C-labeled respiratory substrates for human studies to estimate mitochondrial function in vivo by spectrometry of 13CO2/12CO2 ratio in the exhaled gas [5].

At present, we are interested in the mechanism of toxicity of heavy water (deuterium oxide, D2O). Since the C-D bond is 6-10 times stronger than the C-H bond, the toxicity of D2O has been attributed to the strong kinetic isotope effect of D. When neuronal cells from the mouse brain primary cell culture are exposed to 50% D2O, they are killed within 2 days. When neuronal cells are cultured for 7 days in 10% or 25% D2O, metabolomics analysis by the LC-TOF/MS method revealed a marked decrease in the ATP levels and significant increases in the ADP and AMP levels. We also detected deficiency of NAD[H] and accumulation of NAD[D], which can be explained by addition of [D] from aconitase and fumarase reactions from D2O as well as by transfer of deuterium to NAD[D] by dehydrogenases (IDH, KGD, MDH) in the TCA cycle. The direct effect of NAD[D] on the Complex I activity of respiratory chain should be examined. The inhibitory effect of D+ on the subunit c of FoF1-ATPase should be also considered. In order to understand the mechanisms involving heavy water toxicity in cells and mitochondria, multiomics studies including metabolomics, transcriptomics, and fluxomics will be necessary.


Bioblast editor: Kandolf G O2k-Network Lab: JP Tokyo Tanaka M


Labels: MiParea: Pharmacology;toxicology 


Organism: Mouse  Tissue;cell: Nervous system 




Event: E1, Review 


Affiliations

Tokyo Metropolitan Geriatric Hospital Inst Gerontol, Japan.- mtanaka@tmig.or.jp


References

  1. Tanaka M, Nishigaki Y, Fuku N, Ibi T, Sahashi K, Koga Y (2007) Therapeutic potential of pyruvate therapy for mitochondrial diseases. Mitochondrion 7:399–403.
  2. Fujita Y, Ito M, Kojima T, Yatsuga S, Koga Y, Tanaka M (2015) GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion 20:34–42.
  3. Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, Kojima T, Ito M, Tanaka M, Saiki R, Koga Y (2015) Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol 78:814–23.
  4. Kami K, Fujita Y, Igarashi S, Koike S, Sugawara S, Ikeda S, Sato N, Ito M, Tanaka M, Tomita M, Soga T (2012) Metabolomic profiling rationalized pyruvate efficacy in cybrid cells harboring MELAS mitochondrial DNA mutations. Mitochondrion 12:644–53.
  5. Wu IC, Ohsawa I, Fuku N, Tanaka M (2010) Metabolic analysis of 13C-labeled pyruvate for noninvasive assessment of mitochondrial function. Ann NY Acad Sci 1201:111–20.