Functional Mitochondrial States in Heart Failure: Mechanistic Hypotheses and Therapeutic Testing

Significance: Mitochondrial function links myocardial energy demand to substrate metabolism, calcium handling, redox regulation, and tissue repair. These processes vary within heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, creating opportunities for mechanistic phenotyping across conventional clinical categories. Recent Advances: Human myocardial metabolomics and proteomics reveal heterogeneous metabolic remodeling, while experimental cardiac studies connect organelle dynamics, quality control, contact sites, and immune-cell metabolism to functional adaptation and injury. Contrasting substrate and intervention findings emphasize the importance of direction, cellular origin, and physiological context. Critical Issues: Eight interacting modules organize the measurement space. Five illustrative configurations connect energetic and substrate abnormalities, calcium-transfer defects, and downstream injury or immune activity to research questions. They represent different biological levels and have not been jointly derived or validated in human cohorts. Ferroptotic execution and inflammation require separate measurements; their coupling in human HF remains a hypothesis. Future Directions: We propose a worked research rule, a concrete exploratory biomarker panel, and a validation pathway incorporating tissue provenance, temporal behavior, and randomized treatment interactions. Adequate target engagement without cardiac or clinical benefit can challenge therapeutic relevance or patient selection. Clinical application requires reproducible human measurements that improve treatment decisions and outcomes; validated individual assignment is currently unavailable. Antioxid. Redox Signal. 00, 000–000.