The article "Mitochondrial Dysfunction in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Opportunities" by Giovanna Gallo, Speranza Rubattu, and Massimo Volpe, discusses the role of mitochondrial dysfunction in heart failure (HF). Mitochondrial dysfunction leads to a progressive decline in bioenergetic reserve capacity, shifting energy production from mitochondrial fatty acid oxidation to glycolysis, which is ineffective in increasing energy supply. This adaptive process contributes to a vicious cycle and disease progression. Increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, protein and lipid damage, mitochondrial DNA leakage, and inflammatory responses, leading to cardiac remodeling and failure. Neurohormonal dysregulation, such as angiotensin II and endothelin-1, and sympathetic overactivation further exacerbate ventricular cardiomyocyte hypertrophy and cellular damage. The review explores the pathophysiological mechanisms of mitochondrial dysfunction, including increased oxidative stress and membrane potential perturbations, and their association with HF development and progression. It also highlights the potential of mitochondria as therapeutic targets in managing and recovering from HF, discussing various strategies such as fatty acid metabolic regulators, glucose metabolic modulators, mitochondrial OXPHOS regulators, antioxidants, and mitochondrial quality control regulators. The article concludes by emphasizing the emerging role of mitochondria as a promising therapeutic target in HF.The article "Mitochondrial Dysfunction in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Opportunities" by Giovanna Gallo, Speranza Rubattu, and Massimo Volpe, discusses the role of mitochondrial dysfunction in heart failure (HF). Mitochondrial dysfunction leads to a progressive decline in bioenergetic reserve capacity, shifting energy production from mitochondrial fatty acid oxidation to glycolysis, which is ineffective in increasing energy supply. This adaptive process contributes to a vicious cycle and disease progression. Increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, protein and lipid damage, mitochondrial DNA leakage, and inflammatory responses, leading to cardiac remodeling and failure. Neurohormonal dysregulation, such as angiotensin II and endothelin-1, and sympathetic overactivation further exacerbate ventricular cardiomyocyte hypertrophy and cellular damage. The review explores the pathophysiological mechanisms of mitochondrial dysfunction, including increased oxidative stress and membrane potential perturbations, and their association with HF development and progression. It also highlights the potential of mitochondria as therapeutic targets in managing and recovering from HF, discussing various strategies such as fatty acid metabolic regulators, glucose metabolic modulators, mitochondrial OXPHOS regulators, antioxidants, and mitochondrial quality control regulators. The article concludes by emphasizing the emerging role of mitochondria as a promising therapeutic target in HF.