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September 1, 2026Therapeutic Advances in Rare DiseaseOpen Access

Endothelial–mitochondrial coupling in mitochondrial disease: A systematic review and quantitative synthesis of vascular, biochemical, and oxidative bioenergetic dysfunction

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Why the study?

To evaluate the hypothesis that mitochondrial diseases manifest as a nitric oxide-deficiency endotheliopathy and to define vascular impairment and responsiveness to NO-precursor therapy.

Does nitric oxide synthesis-precursor therapy (l-arginine or l-citrulline) improve vascular reactivity, NO signaling, and myocardial bioenergetics in patients with mitochondrial disease?

Comparison

Mitochondrial disease vs controls and NO-precursor therapy vs baseline

Design

Systematic review and quantitative synthesis

Key result

In a systematic review of 157 individuals, mitochondrial disease was associated with marked endothelial impairment that improved following l-arginine or l-citrulline supplementation.

Authors

JAJosé A. AdamsTKTiffany KoLSL Sultan

Discussion

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Overview

May support nitric oxide precursor trials in mitochondrial disease; extends endothelial dysfunction evidence but leaves clinical adoption open.

Study Design

Type

Systematic Review (n=157)

Structured PICO

Does nitric oxide synthesis-precursor therapy (l-arginine or l-citrulline) improve vascular reactivity, NO signaling, and myocardial bioenergetics in patients with mitochondrial disease?

P
Population
Systematic review of 7 studies comprising 76 subjects with mitochondrial disease and 81 controls (ages 8-63 years) evaluating endothelial and bioenergetic function.
I
Intervention
Nitric oxide synthesis-precursor therapy (l-arginine or l-citrulline supplementation)
C
Comparator
Healthy controls (for disease characterization) and pre-treatment baseline (for therapy response)
O
Outcome
Vascular reactivity (flow-mediated dilation, reactive hyperemia index, passive-leg-movement hyperemia), absolute synthesis rate of NO metabolites, and positron emission tomography (PET)-derived myocardial oxidative indices (k mono, DP/k mono)surrogate

Mitochondrial disease features a reversible NO-deficiency endotheliopathy that can be partially restored with l-arginine or l-citrulline supplementation, highlighting the vascular endothelium as a potential therapeutic target.

Limitations

  • small sample sizes
  • nonrandomized designs

Cite This Study

Adams et al. (2026) conducted a systematic review in Mitochondrial disease (n=157). l-arginine or l-citrulline supplementation vs. Controls or baseline was evaluated on Vascular reactivity, biochemical NO production, and myocardial metabolic imaging. In a systematic review of 157 individuals, mitochondrial disease was associated with marked endothelial impairment that improved following l-arginine or l-citrulline supplementation.

synapsesocial.com/papers/6a9c3a592782e6faf3909156https://doi.org/10.1177/26330040261480132
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Endothelial dysfunction in MELAS improved by l-arginine supplementation2006 · 191 citations
  2. 2Endothelial Dysfunction and the Effect of Arginine and Citrulline Supplementation in Children and Adolescents With Mitochondrial Diseases2020 · 19 citations
  3. 3Mitochondrial cardiomyopathy: bridging molecular mechanisms and clinical frontiers2026 · 2 citations
  4. 4Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide.1990 · 7,062 citations
  5. 5Mitochondrial disease genetics update: recent insights into the molecular diagnosis and expanding phenotype of primary mitochondrial disease2018 · 65 citations