Heart failure with preserved ejection fraction (HFpEF) represents a growing clinical challenge, accounting for more than half of all cases of heart failure, for which there are currently no effective treatments. Emerging evidence identifies mitochondrial dysfunction as a central mechanism linking metabolic comorbidities, systemic inflammation, and energy failure in HFpEF. This review provides a comprehensive overview of the metabolic–mitochondrial mechanisms underlying the pathophysiology of HFpEF. Loss of metabolic flexibility, characterized by reduced fatty acid and glucose oxidation, leads to energy inefficiency, lipid accumulation, and oxidative stress. Structural and functional mitochondrial abnormalities, including damaged cristae, altered fission-fusion dynamics, and impaired oxidative phosphorylation, contribute to diastolic dysfunction and ventricular remodeling. In parallel, chronic inflammation and redox imbalance amplify mitochondrial damage through cytokine- and ROS-mediated pathways, creating a cycle of bioenergetic failure. From a therapeutic perspective, strategies aimed at restoring mitochondrial homeostasis, such as physical training, metabolic modulation, SGLT2 inhibition, ketone supplementation, and mitochondria-targeted antioxidants, show promising preclinical results. However, clinical translation remains limited. Deepening the understanding of mitochondrial metabolism could enable the development of personalized treatments capable of improving outcomes for HFpEF patients.

G protein-coupled receptors (GPCRs) represent a family of membrane proteins that regulate several cellular processes. Among the GPCRs, G protein-coupled receptor kinases (GRKs) regulate downstream signaling pathways and receptor desensitization. GRK2 has gained significant interest due to its cardiovascular physiology and pathological involvement. GRK2’s presence in cardiac tissue and its influence on cardiac function, β-adrenergic signaling, and myocardial remodeling underlies its involvement in cardiovascular diseases such as heart failure and ischemia. GRK2’s canonical role is receptor desensitization, but emerging evidence suggests its involvement in mitochondrial dynamics and bioenergetics, influencing processes such as oxidative phosphorylation, reactive oxygen species production, and apoptosis. Moreover, GRK2’s localization within mitochondria suggests a direct role in regulating mitochondrial health and function. Notably, while GRK2 inhibition seems to be a therapeutic approach to heart failure, its precise role in mitochondrial dynamics and pathology needs further investigation. This review explores the complex relationship between mitochondrial function and GRK2 and clarifies the implications for cardiovascular health. Cardiovascular medicine might greatly benefit from future studies that focus on understanding the processes behind GRK2–mitochondrial crosstalk to develop personalized therapies

Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the FMR1 gene encoding for the RNA-binding protein FMRP, particularly expressed in the brain. This gene expansion can lead to premutation (PM, 56–200 CGGs), full mutation (FM, >200 CGGs), or unmethylated FM (UFM), resulting in neurodegeneration, neurodevelopmental disorders, or no apparent intellectual disability, respectively. To investigate the mitochondrial mechanisms that are involved in the FXD patients, we analyzed mitochondrial morphology and bioenergetics in fibroblasts derived from patients. Donut-shaped mitochondrial morphology and excessive synthesis of critical mitochondrial proteins were detected in FM, PM, and UFM cells. Analysis of mitochondrial oxidative phosphorylation in situ reveals lower respiration in PM fibroblasts. Importantly, mitochondrial permeability transition-dependent apoptosis is sensitized to reactive oxygen species in FM, PM, and UFM models. This study elucidated the mitochondrial mechanisms that are involved in the FXD phenotypes, and indicated altered mitochondrial function and morphology. Importantly, a sensitization to permeability transition and apoptosis was revealed in FXD cells. Overall, our data suggest that mitochondria are novel drug targets to relieve the FXD symptoms.

The harmful effect of a long-term high-fructose diet is well established, but the age-dependent physiological responses that can be triggered by a short-term high-fructose diet in skeletal muscles have not been deeply explored. Therefore, the aim of this work was to compare the alterations in mitochondrial energetic and insulin responsiveness in the skeletal muscle induced by a short-term (2 weeks) fructose feeding in rats of different ages. For this purpose, fructose and uric acid levels, insulin sensitivity, mitochondrial bioenergetics and oxidative status were evaluated in the skeletal muscles from young (30 days old) and adult (90 days old) rats. We showed that, even in the short term, a high-fructose diet has a strong impact on skeletal muscle metabolism, with more marked effects in young rats than in adults ones. In fact, despite both groups showing a decrease in insulin sensitivity, the marked mitochondrial dysfunction was found only in the young rats, thus leading to an increase in the mitochondrial production of ROS, and therefore, in oxidative damage. These findings underscore the need to reduce fructose consumption, especially in young people, to preserve the maintenance of a metabolically healthy status.

Background: Cardiac rehabilitation (CR) is a fundamental pillar in the therapeutic pathway of patients with cardiovascular disease, contributing significantly to improving quality of life and reducing the risk of cardiovascular event recurrence. Over the past decades, this approach has progressively evolved, integrating multidisciplinary strategies based on scientific evidence. This study aimed to conduct a detailed analysis of the anthropometric, clinical, and functional characteristics of patients enrolled in the CR Unit of the San Giovanni di Dio and Ruggi D’Aragona University Hospital in Salerno, with particular attention to therapeutic changes, drug titration, and cognitive assessment. Methods: Specifically, the anthropometric, clinical, laboratory, and instrumental data of 95 patients (age 66.56 ± 0.99 years, 75% male) who underwent the CR program between 2023 and 2025 were analyzed. Results: Patients with various diagnoses were enrolled in the CR program: 17% heart failure, 18% cardiac surgery, 20% acute coronary syndrome, 16% chronic coronary syndrome, 29% dyspnea. The patients had numerous comorbidities and risk factors: 73% arterial hypertension, 77% dyslipidemia, 35% diabetes mellitus, 33% smoking, 13% thyroid dysfunction, 47% CAD, 18% CKD, 16% COPD. At baseline, Cardiopulmonary exercise test (CPET) showed a moderately reduced functional capacity (VO₂ peak pre-CR: 14.29 ± 0.53 mL/min/kg; VO₂% predicted pre-CR: 62.19 ± 2.43%), and a significant improvement was recorded in meters at 6 min walk test (6MWT) post-CR (pre-CR: 306.02 ± 9.93 m vs. post-CR: 378.88 ± 13.37 m; p < 0.05). Notably, 22% of patients had a Qmci score < 49.4 points, indicating an MCI. Finally, the cardiovascular therapy was titrated and adapted; specifically, we recorded a significant increase in the use of SGLT2i therapy (pre-RC 22.00% vs. post-RC 34.00%; p < 0.05). Conclusions: In conclusion, CR proved to be safe and effective in enrolled patients; further studies will be needed to investigate the therapeutic modifications implemented during CR programs in more detail.