Activation of the phenylalanine metabolic axis is associated with adverse clinical outcomes and mitochondria-dependent bioenergetic deficiency in ischemic cardiomyocytes

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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. 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. 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. 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. 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. Not applicable.

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