Trial reportThe Journal of clinical investigation2021
Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity.
Trial report in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
131 citing papers in PubMed, 1 synthesis or guideline pooled it.
- A systematic review on the biochemical threshold of mitochondrial genetic variants.Genome research · 2024Pooled it
- Longitudinal multiomic signatures of ARDS and sepsis inflammatory phenotypes identify pathways associated with mortality.The Journal of clinical investigation · 2026Trial
- Trial
- Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome.bioRxiv : the preprint server for biology · 2026Article
- The Reductive Stress Nexus: Integrated Pathways of Metabolic Dysregulation, Senescence and Blood-Brain Barrier Failure in Neurodegenerative Disease and Brain Aging.Cell biochemistry and biophysics · 2026Review
- Trans-activator of transcription-pre-B-cell leukemia transcription factor 1 alleviates Alzheimer's disease by reducing neuronal insulin resistance and restoring energy homeostasis.Neural regeneration research · 2026Article
- Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.Metabolomics : Official journal of the Metabolomic Society · 2026Article
- Article
- Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.Genes · 2026Review
- Karnofsky performance scale and modified Rankin scale as indicators of functional capacity in patients with mitochondrial disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Article
- Reductive Stress and Ferroptosis: Linking Insulin Signaling to Metabolic Dysfunction.Biomolecules · 2026Review
- From Pharmacodynamic Biomarker to Evaluating Treatment Response: Biomarkers in Primary Mitochondrial Diseases.Clinical and translational science · 2026Review
- Lactate as a Chemical Modification on Proteins and Metabolites.Annual review of biochemistry · 2026Review
- Mapping the GDF15 arm of the integrated stress response in human cells and tissues.Communications biology · 2026Article
- Why is the tumor microenvironment disordered by NADH/NADRedox biology · 2026Review
- A Very-low-energy Fast Involves Increased Adipose Inflammatory Gene Expression: A 6-day Feeding Trial (FASTOMICS-6).The Journal of clinical endocrinology and metabolism · 2026Article
- Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.Journal of neurology · 2026Review
- The Emerging Role of N-Lactoyl-Phenylalanine (Lac-Phe) in Metabolic Regulation and Disease: From Exercise-Induced Metabolite to Therapeutic Candidate.Antioxidants (Basel, Switzerland) · 2026Article
- Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.Pharmacological reports : PR · 2026Article
- Recessive PPTC7 deficiency triggers excessive mitophagy to cause a severe inborn error of metabolism with hypomyelinating leukodystrophy.Research square · 2026Article
71 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
17 authors.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.