Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity.

TitleCirculating markers of NADH-reductive stress correlate with mitochondrial disease severity.
Publication TypeJournal Article
Year of Publication2021
AuthorsSharma R, Reinstadler B, Engelstad K, Skinner OS, Stackowitz E, Haller RG, Clish CB, Pierce K, Walker MA, Fryer R, Oglesbee D, Mao X, Shungu DC, Khatri A, Hirano M, De Vivo DC, Mootha VK
JournalJ Clin Invest
Volume131
Issue2
Date Published2021 01 19
ISSN1558-8238
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Alanine, Biomarkers, Child, Child, Preschool, Female, Growth Differentiation Factor 15, Humans, Hydroxybutyrates, Lactic Acid, Male, MELAS Syndrome, Middle Aged, Mutation, Severity of Illness Index
Abstract

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, β-hydroxy acylcarnitines, and β-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.

DOI10.1172/JCI136055
Alternate JournalJ Clin Invest
PubMed ID33463549
PubMed Central IDPMC7810486
Grant ListF32 GM133047 / GM / NIGMS NIH HHS / United States
P01 HD080642 / HD / NICHD NIH HHS / United States
P30 DK040561 / DK / NIDDK NIH HHS / United States
R01 AR050597 / AR / NIAMS NIH HHS / United States
Related Institute: 
MRI Research Institute (MRIRI)

Weill Cornell Medicine
Department of Radiology
525 East 68th Street New York, NY 10065