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  • Sciforum conference paper
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In Proceedings of the The 2nd International Electronic Conference on Metabolomics 20-27 November 2017; MDPI AG , 2017,
doi: 10.3390/iecm-2-04981

Mutations in mitochondrial membrane proteins could cause physiological and metabolic alterations in mitochondria as well as in cytosol. In order to address the origin of these alterations, mitochondria and cytosol of yeast wild-type BY4741 and two mutants, sdh2Δ and atp4Δ, were isolated from whole cells. These three compartments, namely mitochondria, cytosol and whole cell, were analyzed by gas chromatography-mass spectrometry based metabolic profiling, identifying seventy-three metabolites altogether, from which sixteen or ten were not detected either in mitochondria or cytosol. Compartment-specific distribution and regulation of metabolites were observed, showing the responses to the deletions of sdh2 and atp4. Based on the metabolic signature in mitochondrial matrix and cytosol, both mutants can be discriminated from wild-type by principal component analysis. De letions of electron chain transport components, sdh2 and atp4, altered not only citrate cycle related metabolites, but also diverse metabolites including amino acids, fatty acids, purine and pyrimidine intermediates and others. By applying metabolomics to isolated mitochondria and cytosol, compartment-specific metabolic regulation can be identified, which is helpful in understanding the molecular mechanism of mitochondrial homeostasis in response to genetic mutations.

  • Sciforum conference paper
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In Proceedings of the The 2nd International Electronic Conference on Metabolomics 20-27 November 2017; MDPI AG , 2017,
doi: 10.3390/iecm-2-04982

With a global rise in ageing population and age-associated diseases, understanding how diet modifies cognitive ageing represents key revenues for prevention. Epidemiology suggests inverse associations between specific dietary patterns (i.e. Mediterranean diet) and cognitive decline and neurodegenerative diseases [1-3]- which raises an important question: which dietary bioactives (i.e. metabolites derived from plant foods) are capable of modulating neuronal ageing?

In this discovery (D-CogPlast6) study, we aim to identify a combination of diet-derived metabolites associated with cognitive decline using untargeted metabolomics. We leveraged the Three-City (3C) study (a large French cohort of elderly people) and compared the metabolic profiles of 209 individuals who later developed cognitive decline over 13 years against 209 controls with preserved cognition. Subjects were matched for age at baseline, gender and level of education. Serum samples (collected at the beginning of the cohort study when all participants were cognitively healthy) were profiled using high-resolution UHPLC-QToF (Bruker Impact ll) and raw UHPLC-MS data were processed using Galaxy (WorkFlow4Metabolomics.org). Validated PLS-DA clearly distinguished between case and control populations. To account for the matched case-control study design and for potential confounders (i.e. season of blood sampling, body mass index, and number of medications consumed), sparse conditional logistic regression (with bootstrapped re-sampling) was adapted. 17 ions were representative of a serum metabolomic profile associated with cognition. These ions and their clusters whose intensities were significantly elevated in each of the population groups were annotated using online and in-house databases, literature search and commercial standards. Tandem MS/MS fragmentation is presently in progress for further validation of these ions’ identification.

Next, the robustness of this set of ions will be validated in a separate cohort of 400 subjects. The ability of these ions predictive of cognitive decline to modulate brain plasticity and neuronal integrity will be further investigated in an in vitro parabiosis assay and finally in a proof-of-principle dietary intervention mouse model. It is expected that these identified and validated biomarkers will lead to dietary intervention and recommendations for cognitive decline prevention.

6The D-CogPlast study is funded by JPI-HDHL and AgreenSkills+ Young incoming fellowship.

 

References:

  1. Hardman, R.J., et al., Adherence to a Mediterranean-style diet and effects on cognition in adults: a qualitative evaluation and systemic review of longitudinal and prospective trials. Frontiers in Nutrition, 2016. 3(22): p. 1-13.
  2. Pelletier, A., et al., Mediterranean diet and preserved brain structural connectivity in older subjects. Alzheimer's & Dementia, 2015. 11(9): p. 1023-1031.
  3. Singh, B., et al., Association of mediterranean diet with mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis. Journal of Alzheimer's Disease, 2014. 39(2): p. 271-282.
  • Sciforum conference paper
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In Proceedings of the The 2nd International Electronic Conference on Metabolomics 20-27 November 2017; MDPI AG , 2017,
doi: 10.3390/iecm-2-04983

The importance of adenosine and ATP in regulating many biological functions has long been recognized, especially for their effects on the cardiovascular homeostasis which may be used for management of hypertension and cardiovascular diseases. In response to ischemia and cardiovascular injury, ATP is broken down to release adenosine. The activity of adenosine is very short lived because it is rapidly taken up by myocardial and endothelial cells, erythrocytes (RBC), and also rapidly metabolized to oxypurine metabolites and other adenine nucleotides. Extra-cellular and intracellular ATP is broken down rapidly to ADP and AMP and finally to adenosine by 5’-nucleotidase. These metabolic events are known to occur in the myocardium, endothelium as well as in RBC. Exercise has been shown to increase metabolism of ATP in the RBC which may be an important mechanism for post exercise hypotension and cardiovascular protection. The post exercise effect was greater in hypertensive than in normotensive rats. The review summarizes current evidence in support of ATP metabolism in the RBC as potential systemic biomarker for cardiovascular protection and toxicities. It also discusses the opportunities, challenges and obstacles of exploiting ATP metabolism in RBC as target for drug development.

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