Mitochondrial Pathophysiology of Heart Failure with Reduced Ejection Fraction: From Quality Control Failure to Emerging Therapies

Chronic heart failure with reduced ejection fraction (HFrEF) is increasingly understood as a disorder of cardiac energy conversion in which mitochondria fail both as the principal source of ATP and as regulators of calcium handling, redox balance, cell survival and sterile inflammation.This narrative review synthesizes evidence published between 2021 and 2026 on mitochondrial pathophysiology in HFrEF, with emphasis on human myocardium and cardiovascular aging.Human studies converge on a reproducible energetic signature: a 20% reduction in the phosphocreatine to ATP ratio, depletion of the adenine nucleotide pool, a collapse of creatine kinase flux, reduced fatty acid import and oxidation, glycolysis uncoupled from glucose oxidation, increased ketone and lactate consumption, defective branched-chain amino acid catabolism, hyperacetylation of mitochondrial enzymes and myocardial iron deficiency.These lesions are coupled to failure of mitochondrial quality control (fragmentation, cristae