Recent studies increasingly highlight profound metabolic remodeling within the HFpEF heart; however, it remains unclear if this is an intrinsic or systemic phenomenon. In the present study, we identify dicarbonyl and glycative stress as key drivers of mitochondrial dysfunction in an ANGII/PE mouse model with HFpEF phenotype independent of systemic metabolic disease. These findings reveal a previously unrecognized metabolic-mitochondrial axis and suggest dicarbonyl detoxification and mitochondrial antiglycation as potential therapeutic targets.

Neutrophilic inflammation constitutes a major pathology in cystic fibrosis (CF), a life-shortening genetic disorder. However, the underlying mechanisms remain incompletely understood. Here we report our investigation into CF neutrophil recruitment, apoptosis and clearance to determine if any neutrophil intrinsic defect is involved in the pathogenesis. Congenic fluorescent wild-type (WT) and CF mice were generated and used as bone marrow (BM) donors. Non-fluorescent WT and CF recipients were transplanted with a mixture of EGFP-WT and DsRed-CF BM cells and interrogated for neutrophil recruitment and apoptosis in the same lung after zymosan challenge. Additionally, ex vivo neutrophil migration and apoptosis were also examined to confirm the in vivo findings. Moreover, DsRed-WT or DsRed-CF BM cells were transfused into non-fluorescent CF recipients that had been intratracheally challenged with zymosan. Percentages of apoptotic cell-laden macrophages in the lungs were compared. The data indicate that CF and WT neutrophils exhibited a similar migratory capacity and were equally recruited to the same lung, regardless of the recipient phenotype. However, CF neutrophils displayed a significantly delayed apoptosis. Such an anomaly was linked to reduced hypochlorous acid production. Moreover, CF macrophages exhibited a significantly higher expression of efferocytosis marker MerTK, and a greater capacity of efferocytosis, implying that macrophage phagocytosis of apoptotic cells is not impaired in this experimental setting. These findings suggest that intrinsically dysregulated programmed cell death affects CF neutrophil fate decision and fuels neutrophilic inflammation in CF lungs.

Doxorubicin (DOX) remains an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Mitochondrial dysfunction and metabolic remodeling are central features of DOX-induced cardiac injury. ATP synthase inhibitory factor-1 (IF1) is an endogenous inhibitor of the hydrolytic activity of mitochondrial ATP synthase and has emerged as an important regulator of cellular bioenergetics. Cardiac IF1 expression is increased in multiple pathological conditions; however, its role in chemotherapy-induced cardiotoxicity remains unclear. Here, we investigated the contribution of IF1 to DOX-induced cardiotoxicity using male C57BL/6J wild-type (WT) and IF1 knockout (IF1KO) mice, isolated cardiac mitochondria, cultured neonatal cardiomyocytes, and AC16 human cardiomyocytes. Cardiac function was assessed by echocardiography, mitochondrial function by high-resolution respirometry and Seahorse metabolic flux analysis, and myocardial injury by histological and ultrastructural analyses. DOX treatment markedly increased cardiac IF1 protein levels despite reduced IF1 mRNA expression. IF1 deficiency enhanced mitochondrial respiration in isolated cardiac mitochondria and cultured cardiomyocytes under both basal and DOX-stressed conditions. IF1KO mice exhibited attenuated cardiac dysfunction and improved myocardial ultrastructure following DOX treatment compared with WT mice. In AC16 cardiomyocytes exposed to DOX, overexpression of WT IF1 improved cellular metabolic activity but provided only limited preservation of mitochondrial respiratory capacity. In contrast, overexpression of the dominant-negative IF1 mutant (IF1E30A) not only improved metabolic activity but also preserved mitochondrial respiration. These findings identify IF1 as a key regulator of metabolic adaptation during DOX stress. Upregulation of functional IF1 may represent an adaptive response that promotes glycolytic ATP production during mitochondrial stress, whereas inhibition of IF1 activity preserves metabolic activity primarily through maintenance of mitochondrial function. Collectively, these findings provide new insights into the role of IF1 in DOX-induced cardiomyopathy and highlight IF1 as a potential therapeutic target in cardio-oncology.