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Cell Rep. 2015 Nov 3;13(5):981-9. doi: 10.1016/j.celrep.2015.09.054. Epub 2015 Oct 22.

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

Author information

1
Department of Nutrition, Université de Montréal, Montreal, QC H3C 3J7, Canada; Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.
2
Department of Systems Biology, Harvard Medical School, Boston, MA 02445, USA.
3
Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada.
4
Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada; Centre de Santé et de Services Sociaux de Chicoutimi, Chicoutimi, QC G7H 5H6, Canada.
5
Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.
6
Broad Institute, Cambridge, MA 02142, USA.
7
Medical Genetics Service, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
8
The LSFC Consortium.
9
Centre de Santé et de Services Sociaux de Chicoutimi, Chicoutimi, QC G7H 5H6, Canada.
10
Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.
11
Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02445, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: vamsi@hms.harvard.edu.
12
Department of Nutrition, Université de Montréal, Montreal, QC H3C 3J7, Canada; Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada. Electronic address: christine.des.rosiers@umontreal.ca.

Abstract

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. To gain insight into the systemic, biochemical consequences of respiratory chain dysfunction, we performed a case-control, prospective metabolic profiling study in a genetically homogenous cohort of patients with Leigh syndrome French Canadian variant, a mitochondrial respiratory chain disease due to loss-of-function mutations in LRPPRC. We discovered 45 plasma and urinary analytes discriminating patients from controls, including classic markers of mitochondrial metabolic dysfunction (lactate and acylcarnitines), as well as unexpected markers of cardiometabolic risk (insulin and adiponectin), amino acid catabolism linked to NADH status (α-hydroxybutyrate), and NAD(+) biosynthesis (kynurenine and 3-hydroxyanthranilic acid). 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.

PMID:
26565911
PMCID:
PMC4644511
DOI:
10.1016/j.celrep.2015.09.054
[Indexed for MEDLINE]
Free PMC Article

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