Activation of the phenylalanine metabolic axis is associated with adverse clinical outcomes and mitochondria-dependent bioenergetic deficiency in ischemic cardiomyocytes
6 affiliations
- 1School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
- 2Heart Failure Research Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
- 3Department of Nursing, Chang Gung Memorial Hospital, Keelung, Taiwan
- 4Department of Biochemistry and Molecular Biology, Chang Gung University, Taoyuan, Taiwan
- 5Institute of Bioinformatics and Structural Biology, School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
- 6College of Medicine, Chang Gung University, Taoyuan, Taiwan
Abstract
Background: Elevated plasma phenylalanine (PHE) is associated with adverse outcomes in heart failure (HF), but whether PHE is only a marker of systemic severity or can modify ischemic vulnerability remains unclear.
Objectives: We evaluated the prognostic value of the PHE–phenylpyruvate (PPA) axis and examined how PHE affects mitochondrial stress responses after ischemic injury and whether 5-methoxytryptophan (5-MTP) mitigates these effects.
Methods: Plasma levels of PHE and PPA were analyzed in 191 patients with ischemic HF from the cardiac intensive care unit to assess 90-day mortality. A rat myocardial infarction (MI) model was used to assess PHE-related metabolites in infarct and peri-infarct-enriched left ventricular tissue during chronic post-MI remodeling. HL-1 cardiomyocytes were subjected to oxygen–serum–glucose deprivation (OSGD) with or without PHE and 5-MTP. Cell metabolic activity, ATP levels, mitochondrial respiration, extracellular acidification rate-defined glycolytic function, pyruvate supplementation, dichloroacetate response, cell-death patterns, intracellular PHE-related metabolites, and quantitative proteomics were analyzed.
Results: In the clinical cohort, elevated PHE was independently associated with 90-day mortality after adjustment for estimated glomerular filtration rate, C-reactive protein, and albumin, supporting PHE as a short-term prognostic and candidate risk-stratification biomarker. Post-MI myocardium showed tissue-level accumulation of PHE-related metabolites. In HL-1 cells, 20 mM PHE exacerbated OSGD-induced mitochondrial dysfunction, ATP reduction, glycolytic reserve exhaustion, and mixed cell-death signaling. Pyruvate failed to rescue ATP, while dichloroacetate partially restored ATP, suggesting pyruvate dehydrogenase-sensitive vulnerability. Proteomics revealed pathway-level suppression of oxidative phosphorylation; 5-MTP partially shifted mitochondrial and metabolic signatures toward recovery without uniformly lowering intracellular PHE.
Conclusions: PHE is a short-term prognostic marker and, under high-dose experimental stress, a potential modifier of ischemic bioenergetic vulnerability. 5-MTP appears to act mainly through downstream mitochondrial stress resilience. These findings support PHE-related metabolic stress as a clinically relevant risk signal and experimental modifier of ischemic myocardial vulnerability, while further validation is required before PHE-guided therapeutic strategies can be proposed.
Clinical trial number: Not applicable.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13062-026-00949-3.
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BibTeX
@article{hsu2026activation,
title = {{Activation of the phenylalanine metabolic axis is associated with adverse clinical outcomes and mitochondria-dependent bioenergetic deficiency in ischemic cardiomyocytes}},
author = {Wan-Tseng Hsu and Min-Hui Liu and Kun-Yi Chien and Chi-Ying Lee and Yung-Jen Chuang and Chao-Hung Wang},
journal = {Biology Direct},
year = {2026},
month = sep,
doi = {10.1186/s13062-026-00949-3},
url = {https://doi.org/10.1186/s13062-026-00949-3},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Activation of the phenylalanine metabolic axis is associated with adverse clinical outcomes and mitochondria-dependent bioenergetic deficiency in ischemic cardiomyocytes
AU - Wan-Tseng Hsu
AU - Min-Hui Liu
AU - Kun-Yi Chien
AU - Chi-Ying Lee
AU - Yung-Jen Chuang
AU - Chao-Hung Wang
PY - 2026
DA - 2026/09/05
JO - Biology Direct
DO - 10.1186/s13062-026-00949-3
UR - https://doi.org/10.1186/s13062-026-00949-3
AB - Background: Elevated plasma phenylalanine (PHE) is associated with adverse outcomes in heart failure (HF), but whether PHE is only a marker of systemic severity or can modify ischemic vulnerability remains unclear. Objectives: We evaluated the prognostic value of the PHE–phenylpyruvate (PPA) axis and examined how PHE affects mitochondrial stress responses after ischemic injury and whether 5-methoxytryptophan (5-MTP) mitigates these effects. Methods: Plasma levels of PHE and PPA were analyzed in 191 patients with ischemic HF from the cardiac intensive care unit to assess 90-day mortality. A rat myocardial infarction (MI) model was used to assess PHE-related metabolites in infarct and peri-infarct-enriched left ventricular tissue during chronic post-MI remodeling. HL-1 cardiomyocytes were subjected to oxygen–serum–glucose deprivation (OSGD) with or without PHE and 5-MTP. Cell metabolic activity, ATP levels, mitochondrial respiration, extracellular acidification rate-defined glycolytic function, pyruvate supplementation, dichloroacetate response, cell-death patterns, intracellular PHE-related metabolites, and quantitative proteomics were analyzed. Results: In the clinical cohort, elevated PHE was independently associated with 90-day mortality after adjustment for estimated glomerular filtration rate, C-reactive protein, and albumin, supporting PHE as a short-term prognostic and candidate risk-stratification biomarker. Post-MI myocardium showed tissue-level accumulation of PHE-related metabolites. In HL-1 cells, 20 mM PHE exacerbated OSGD-induced mitochondrial dysfunction, ATP reduction, glycolytic reserve exhaustion, and mixed cell-death signaling. Pyruvate failed to rescue ATP, while dichloroacetate partially restored ATP, suggesting pyruvate dehydrogenase-sensitive vulnerability. Proteomics revealed pathway-level suppression of oxidative phosphorylation; 5-MTP partially shifted mitochondrial and metabolic signatures toward recovery without uniformly lowering intracellular PHE. Conclusions: PHE is a short-term prognostic marker and, under high-dose experimental stress, a potential modifier of ischemic bioenergetic vulnerability. 5-MTP appears to act mainly through downstream mitochondrial stress resilience. These findings support PHE-related metabolic stress as a clinically relevant risk signal and experimental modifier of ischemic myocardial vulnerability, while further validation is required before PHE-guided therapeutic strategies can be proposed. Clinical trial number: Not applicable. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13062-026-00949-3.
SN - 1745-6150
ER -