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A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome.

Thompson Legault J, Strittmatter L, Tardif J, Sharma R, Tremblay-Vaillancourt V, Aubut C, Boucher G, Clish CB, Cyr D, Daneault C, Waters PJ, LSFC ConsortiumVachon L, Morin C, Laprise C, Rioux JD, Mootha VK, Des Rosiers C - Cell Rep (2015)

Bottom Line: A decline in mitochondrial respiration represents the root cause of a large number of inborn errors of metabolism.It is also associated with common age-associated diseases and the aging process.Our study identifies systemic, metabolic pathway derangements that can lie downstream of primary mitochondrial lesions, with implications for understanding how the organelle contributes to rare and common diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutrition, Université de Montréal, Montreal, QC H3C 3J7, Canada; Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.

No MeSH data available.


Related in: MedlinePlus

Quantitative Profiling of Metabolites Reflective of NADH/NAD+ Redox StatusMetabolites are shown in scatter dot plots with line indicating the mean. *p < 0.05 patients versus controls. See also Table S2 for raw data.
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Figure 3: Quantitative Profiling of Metabolites Reflective of NADH/NAD+ Redox StatusMetabolites are shown in scatter dot plots with line indicating the mean. *p < 0.05 patients versus controls. See also Table S2 for raw data.

Mentions: Because both PCA and permutation tests revealed that a perturbed redox status was a prominent feature of the distinctive metabolic signature in LSFC patients, an isotope dilution GC-MS method was developed in order to quantify with precision lactate and β-hydroxybutyrate as well as their corresponding oxidized counterparts, namely pyruvate and acetoacetate, respectively. In addition, we included α-hydroxybutyrate, a finding issued from the metabolic profiling on Platform 2 but that was not assessed on Platform 1, because we suspected that its elevation was also linked to the increased NADH/NAD+ ratio. Hence, it was measured along with its oxidized counterpart, namely α-ketobutyrate. The results of these analyses are consistent with the initial metabolic profiling data. In fact, the plasma concentration of lactate, pyruvate, β-hydroxybutyrate, and α-hydroxybutyrate, as well as the lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios, were all significantly higher in LSFC patients (Figure 3). Importantly, this analysis revealed that the α-hydroxybutyrate/α-ketobutyrate ratio was also significantly increased. Collectively, these quantitative measurements further support the findings of an elevated plasma level of α-hydroxybutyrate in LSFC patients, revealing an additional metabolic perturbation linked to the altered redox status in these patients.


A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome.

Thompson Legault J, Strittmatter L, Tardif J, Sharma R, Tremblay-Vaillancourt V, Aubut C, Boucher G, Clish CB, Cyr D, Daneault C, Waters PJ, LSFC ConsortiumVachon L, Morin C, Laprise C, Rioux JD, Mootha VK, Des Rosiers C - Cell Rep (2015)

Quantitative Profiling of Metabolites Reflective of NADH/NAD+ Redox StatusMetabolites are shown in scatter dot plots with line indicating the mean. *p < 0.05 patients versus controls. See also Table S2 for raw data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644511&req=5

Figure 3: Quantitative Profiling of Metabolites Reflective of NADH/NAD+ Redox StatusMetabolites are shown in scatter dot plots with line indicating the mean. *p < 0.05 patients versus controls. See also Table S2 for raw data.
Mentions: Because both PCA and permutation tests revealed that a perturbed redox status was a prominent feature of the distinctive metabolic signature in LSFC patients, an isotope dilution GC-MS method was developed in order to quantify with precision lactate and β-hydroxybutyrate as well as their corresponding oxidized counterparts, namely pyruvate and acetoacetate, respectively. In addition, we included α-hydroxybutyrate, a finding issued from the metabolic profiling on Platform 2 but that was not assessed on Platform 1, because we suspected that its elevation was also linked to the increased NADH/NAD+ ratio. Hence, it was measured along with its oxidized counterpart, namely α-ketobutyrate. The results of these analyses are consistent with the initial metabolic profiling data. In fact, the plasma concentration of lactate, pyruvate, β-hydroxybutyrate, and α-hydroxybutyrate, as well as the lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios, were all significantly higher in LSFC patients (Figure 3). Importantly, this analysis revealed that the α-hydroxybutyrate/α-ketobutyrate ratio was also significantly increased. Collectively, these quantitative measurements further support the findings of an elevated plasma level of α-hydroxybutyrate in LSFC patients, revealing an additional metabolic perturbation linked to the altered redox status in these patients.

Bottom Line: A decline in mitochondrial respiration represents the root cause of a large number of inborn errors of metabolism.It is also associated with common age-associated diseases and the aging process.Our study identifies systemic, metabolic pathway derangements that can lie downstream of primary mitochondrial lesions, with implications for understanding how the organelle contributes to rare and common diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutrition, Université de Montréal, Montreal, QC H3C 3J7, Canada; Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.

No MeSH data available.


Related in: MedlinePlus