Polystyrene nanoplastics induce cardiotoxicity by driving myocardial metabolic reprogramming via the SDHA/Succinate/HIF-1α axis.

Polystyrene nanoparticle (PS-NP) exposure induced pronounced structural and functional cardiac injury in mice in vivo.

• Study used an in vivo mouse model alongside AC16 cardiomyocytes and a human cardiac organoid-on-a-chip (COoC) platform.
• Structural and functional cardiac injury was described as 'pronounced' following PS-NP exposure.
• The multi-dimensional approach combined animal models, cell lines, and a human organoid platform to evaluate cardiotoxicity.

PS-NP exposure caused impaired myocardial contraction, disrupted calcium transients, and increased injury biomarkers in vitro.

• Effects were observed in AC16 cardiomyocytes and the cardiac organoid-on-a-chip (COoC) platform.
• Disrupted calcium transients indicate interference with the fundamental electromechanical coupling process in heart muscle cells.
• Elevated injury biomarkers were detected alongside the functional deficits.

PS-NP exposure perturbed myocardial energy metabolism, producing a metabolic reprogramming profile characterized by suppressed fatty acid oxidation (FAO) and enhanced glycolytic activity.

• Fatty acid oxidation, the predominant energy source in healthy cardiac tissue, was suppressed following PS-NP exposure.
• Glycolytic activity was enhanced, representing a shift toward a less efficient anaerobic energy pathway.
• This metabolic reprogramming pattern mirrors pathological remodeling seen in failing hearts.

Activation of fatty acid oxidation or promotion of mitochondrial pyruvate oxidation improved myocardial energy status and alleviated PS-NP-induced cardiotoxicity.

• Metabolic interventions were used experimentally to probe the functional consequences of the observed metabolic reprogramming.
• Both FAO activation and mitochondrial pyruvate oxidation promotion were protective interventions.
• These findings suggest that restoring oxidative metabolism can counteract PS-NP-induced cardiac injury.

Direct inhibition of glycolysis aggravated energy depletion and cellular injury, indicating that enhanced glycolysis provided partial energetic compensation that was insufficient to offset impaired oxidative metabolism.

• Glycolytic inhibition worsened outcomes, demonstrating that the upregulated glycolysis served a compensatory protective role.
• The compensation was described as 'partial' and 'insufficient to offset impaired oxidative metabolism.'
• This finding clarifies the functional role of the metabolic shift rather than treating it as purely pathological.

PS-NP-induced downregulation of SDHA promoted succinate accumulation and HIF-1α stabilization, thereby rewiring myocardial energy metabolism and contributing to cardiac dysfunction.

• SDHA (succinate dehydrogenase subunit A) downregulation was identified as an upstream driver of the metabolic changes.
• Reduced SDHA activity leads to succinate accumulation, as SDHA normally converts succinate to fumarate in the TCA cycle.
• Accumulated succinate stabilizes HIF-1α (hypoxia-inducible factor 1-alpha) by inhibiting prolyl hydroxylases that would otherwise target HIF-1α for degradation.
• HIF-1α stabilization is known to transcriptionally suppress fatty acid oxidation genes and upregulate glycolytic genes, consistent with the observed metabolic reprogramming.

The SDHA/succinate/HIF-1α signaling axis was identified as the key molecular mechanism linking PS-NP exposure to myocardial metabolic reprogramming and cardiotoxicity.

• The axis represents a mechanistic chain: PS-NPs → SDHA downregulation → succinate accumulation → HIF-1α stabilization → metabolic reprogramming → cardiac dysfunction.
• The authors describe this axis as 'a potential molecular link between PS-NPs exposure and cardiac injury.'
• Myocardial metabolic reprogramming was identified as 'an important mechanism underlying PS-NPs-induced cardiotoxicity.'