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Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity.
Sharma, Rohit; Reinstadler, Bryn; Engelstad, Kristin; Skinner, Owen S; Stackowitz, Erin; Haller, Ronald G; Clish, Clary B; Pierce, Kerry; Walker, Melissa A; Fryer, Robert; Oglesbee, Devin; Mao, Xiangling; Shungu, Dikoma C; Khatri, Ashok; Hirano, Michio; De Vivo, Darryl C; Mootha, Vamsi K.
Afiliación
  • Sharma R; Howard Hughes Medical Institute, Department of Molecular Biology, and.
  • Reinstadler B; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Engelstad K; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
  • Skinner OS; Broad Institute, Cambridge, Massachusetts, USA.
  • Stackowitz E; Howard Hughes Medical Institute, Department of Molecular Biology, and.
  • Haller RG; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Clish CB; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
  • Pierce K; Broad Institute, Cambridge, Massachusetts, USA.
  • Walker MA; Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
  • Fryer R; Howard Hughes Medical Institute, Department of Molecular Biology, and.
  • Oglesbee D; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Mao X; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
  • Shungu DC; Broad Institute, Cambridge, Massachusetts, USA.
  • Khatri A; Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
  • Hirano M; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • De Vivo DC; Institute for Exercise and Environmental Medicine of Texas Health Presbyterian Hospital, Dallas, Texas, USA.
  • Mootha VK; Broad Institute, Cambridge, Massachusetts, USA.
J Clin Invest ; 131(2)2021 01 19.
Article en En | MEDLINE | ID: mdl-33463549
Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and because we currently lack facile markers of severity. The m.3243A>G variant is the most common heteroplasmic mitochondrial DNA mutation and underlies a spectrum of diseases, notably mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). To identify robust circulating markers of m.3243A>G disease, we first performed discovery proteomics, targeted metabolomics, and untargeted metabolomics on plasma from a deeply phenotyped cohort (102 patients, 32 controls). In a validation phase, we measured concentrations of prioritized metabolites in an independent cohort using distinct methods. We validated 20 analytes (1 protein, 19 metabolites) that distinguish patients with MELAS from controls. The collection includes classic (lactate, alanine) and more recently identified (GDF-15, α-hydroxybutyrate) mitochondrial markers. By mining untargeted mass-spectra we uncovered 3 less well-studied metabolite families: N-lactoyl-amino acids, ß-hydroxy acylcarnitines, and ß-hydroxy fatty acids. Many of these 20 analytes correlate strongly with established measures of severity, including Karnofsky status, and mechanistically, nearly all markers are attributable to an elevated NADH/NAD+ ratio, or NADH-reductive stress. Our work defines a panel of organelle function tests related to NADH-reductive stress that should enable classification and monitoring of mitochondrial disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome MELAS Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Adolescent / Adult / Aged / Aged80 / Child / Child, preschool / Female / Humans / Male / Middle aged Idioma: En Revista: J Clin Invest Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome MELAS Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Adolescent / Adult / Aged / Aged80 / Child / Child, preschool / Female / Humans / Male / Middle aged Idioma: En Revista: J Clin Invest Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos