title: A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome
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.
authors.affiliation: Department of Nutrition, Université de Montréal, Montreal, QC H3C 3J7, Canada; Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Thompson Legault
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02445, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Strittmatter
authors.affiliation: Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tardif
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02445, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Tremblay-Vaillancourt
authors.affiliation: 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.
authors.forename: Chantale
authors.initials: C
authors.lastname: Aubut
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Boucher
authors.affiliation: Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Medical Genetics Service, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Cyr
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Daneault
authors.affiliation: Medical Genetics Service, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Waters
authors.affiliation: The LSFC Consortium.
authors.forename: Luc
authors.initials: L
authors.lastname: Vachon
authors.affiliation: Centre de Santé et de Services Sociaux de Chicoutimi, Chicoutimi, QC G7H 5H6, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Morin
authors.affiliation: Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.affiliation: Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; Research Centre, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.affiliation: 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.
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.affiliation: 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
mesh_terms: D052242:Adiponectin / Q000097:blood; D000293:Adolescent; D000328:Adult; D000588:Amines / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000652:urine; D016022:Case-Control Studies; D002648:Child; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D007888:Leigh Disease / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D050356:Lipid Metabolism; D008297:Male; D055442:Metabolome; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics
chemical_list: D052242:Adiponectin; D000588:Amines; D015415:Biomarkers; D007328:Insulin; C087940:LRPPRC protein, human; D009363:Neoplasm Proteins; D009243:NAD