Limits...
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

Pathway Relationship of Major Metabolic Alterations in LSFC PatientsThis scheme depicts pathways related to reported perturbations in cytosolic and mitochondrial NADH accumulation, disrupted citric acid cycle (CAC), fatty acid β-oxidation, and amino acid metabolism, with a specific emphasis on those linked to α-hydroxybutyrate formation. Metabolites whose levels increased are indicated in red and with an upward arrow; those whose levels decreased are indicated in green and with a downward arrow. Metabolites whose levels did not change significantly are indicated in black with a sideways arrow. Those metabolites that were not measured are indicated in black (with no arrow). See also Figure S1 for an overview of analytes measured in the study and Table S2 for raw data and p values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4644511&req=5

Figure 4: Pathway Relationship of Major Metabolic Alterations in LSFC PatientsThis scheme depicts pathways related to reported perturbations in cytosolic and mitochondrial NADH accumulation, disrupted citric acid cycle (CAC), fatty acid β-oxidation, and amino acid metabolism, with a specific emphasis on those linked to α-hydroxybutyrate formation. Metabolites whose levels increased are indicated in red and with an upward arrow; those whose levels decreased are indicated in green and with a downward arrow. Metabolites whose levels did not change significantly are indicated in black with a sideways arrow. Those metabolites that were not measured are indicated in black (with no arrow). See also Figure S1 for an overview of analytes measured in the study and Table S2 for raw data and p values.

Mentions: Beyond markers of mitochondrial energy metabolic pathways, other unexpected changes reflecting perturbations in the metabolism of several amino acids were observed in LSFC patients. These include higher plasma levels of α-hydroxybutyrate. However, its oxidized metabolite counterpart, namely α-ketobutyrate, which arises from the catabolism of the essential amino acids threonine and/or methionine in the cytosol (Landaas, 1975), did not differ; consequently, the α-hydroxybutyrate/α-ketobutyrate ratio was also significantly elevated. Whereas these findings likely represent another consequence of an elevated NADH/NAD+ ratio, the higher level of α-hydroxybutyrate also highlights major critical perturbations in its metabolism. The latter is depicted in Figure 4 along with changes in closely related metabolites. Similarly to pyruvate, α-ketobutyrate is at a metabolic crossroad between the cytosol and the mitochondria. It may be transported to the mitochondria and subjected to oxidative decarboxylation to form propionyl-CoA; these steps are likely catalyzed by the pyruvate transporter and the branched-chain α-keto acid dehydrogenase complex (Jakobs et al., 1977; Paxton et al., 1986; Smith and Strang, 1958; Steele et al., 1984). Alternatively, α-ketobutyrate may be reduced to α-hydroxybutyrate by lactate dehydrogenase or β-hydroxybutyrate dehydrogenase (Rosalki and Wilkinson, 1960).


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)

Pathway Relationship of Major Metabolic Alterations in LSFC PatientsThis scheme depicts pathways related to reported perturbations in cytosolic and mitochondrial NADH accumulation, disrupted citric acid cycle (CAC), fatty acid β-oxidation, and amino acid metabolism, with a specific emphasis on those linked to α-hydroxybutyrate formation. Metabolites whose levels increased are indicated in red and with an upward arrow; those whose levels decreased are indicated in green and with a downward arrow. Metabolites whose levels did not change significantly are indicated in black with a sideways arrow. Those metabolites that were not measured are indicated in black (with no arrow). See also Figure S1 for an overview of analytes measured in the study and Table S2 for raw data and p values.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Pathway Relationship of Major Metabolic Alterations in LSFC PatientsThis scheme depicts pathways related to reported perturbations in cytosolic and mitochondrial NADH accumulation, disrupted citric acid cycle (CAC), fatty acid β-oxidation, and amino acid metabolism, with a specific emphasis on those linked to α-hydroxybutyrate formation. Metabolites whose levels increased are indicated in red and with an upward arrow; those whose levels decreased are indicated in green and with a downward arrow. Metabolites whose levels did not change significantly are indicated in black with a sideways arrow. Those metabolites that were not measured are indicated in black (with no arrow). See also Figure S1 for an overview of analytes measured in the study and Table S2 for raw data and p values.
Mentions: Beyond markers of mitochondrial energy metabolic pathways, other unexpected changes reflecting perturbations in the metabolism of several amino acids were observed in LSFC patients. These include higher plasma levels of α-hydroxybutyrate. However, its oxidized metabolite counterpart, namely α-ketobutyrate, which arises from the catabolism of the essential amino acids threonine and/or methionine in the cytosol (Landaas, 1975), did not differ; consequently, the α-hydroxybutyrate/α-ketobutyrate ratio was also significantly elevated. Whereas these findings likely represent another consequence of an elevated NADH/NAD+ ratio, the higher level of α-hydroxybutyrate also highlights major critical perturbations in its metabolism. The latter is depicted in Figure 4 along with changes in closely related metabolites. Similarly to pyruvate, α-ketobutyrate is at a metabolic crossroad between the cytosol and the mitochondria. It may be transported to the mitochondria and subjected to oxidative decarboxylation to form propionyl-CoA; these steps are likely catalyzed by the pyruvate transporter and the branched-chain α-keto acid dehydrogenase complex (Jakobs et al., 1977; Paxton et al., 1986; Smith and Strang, 1958; Steele et al., 1984). Alternatively, α-ketobutyrate may be reduced to α-hydroxybutyrate by lactate dehydrogenase or β-hydroxybutyrate dehydrogenase (Rosalki and Wilkinson, 1960).

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