Doxorubicin induces an acute hypermetabolic state in cardiac cells that progresses to maladaptation and chronic dysfunction, mitigated by targeting the PI3Kγ–PDK4–PDH axis.
Does targeting the PI3Kγ-PDK4-PDH axis prevent doxorubicin-induced metabolic maladaptation and cardiotoxicity in mice?
Doxorubicin induces an initial hypermetabolic state that becomes maladaptive, but targeting the PI3Kγ-PDK4-PDH axis can prevent these chronic metabolic alterations and potential cardiotoxicity.
Tasa de eventos absoluta: 0% vs 0%
Abstract Abstract Doxorubicin (DOX) is a highly effective chemotherapeutic agent limited by dose-dependent cardiotoxicity. A key pathogenic event involves mitochondrial accumulation in cardiomyocytes, however, the resulting metabolic adaptations remain poorly understood. Therefore, this study characterizes DOX-induced alterations in cardiac metabolism and highlights their potential as novel therapeutic targets. Methods Female BALB/c mice received DOX over two weeks (12 mg/kg) and were sacrificed at early (3 days) or late (6 weeks) timepoints. Cardiac metabolism was assessed by metabolomics, 13C₆-glucose flux analysis, proteomics and metabolic enzymes activity in whole hearts and isolated mitochondria. Oxygen consumption was measurd in vitro (Seahorse) and ex vivo (Oroboros). The contribution to DOX-induced metabolic rewiring of PI3Kγ, that has been previously showed to be activated by DOX, was studied in mice expressing a kinase-inactive enzyme (PI3Kγ kinase-dead; KD). To unravel the role of PDK4-PDH axis, PDK4 overexpression was induced in mice using AAV9 viral vector, followed by DOX treatment. Results Following acute DOX administration, hearts exhibited an unexpected hypermetabolic response characterized by increased mitochondrial respiration and enhanced substrate flexibility, particularly for glucose, as confirmed by 13C₆-glucose tracing. Untargeted metabolomics revealed pyruvate depletion and acetyl-CoA accumulation, accompanied by altered protein acetylation, as evidenced by proteomics for lysine acetylation, and buildup of TCA intermediates. These changes, together with increased glutamine utilization reminiscent of cancer cell metabolism, marked an acute adaptive response. However, the persistence of this hypermetabolic state led to maladaptation, resulting in mitochondrial overload, energetic uncoupling, oxidative stress, and ultimately cardiac dysfunction. Notably, inhibition of the PI3Kγ–PDK4–PDH axis, either through PI3Kγ blockade or PDK4 overexpression, fully prevented chronic metabolic alterations, identifying PI3Kγ as a key regulator of substrate selection and metabolic remodeling during DOX treatment. Metabolic rewiring also involved cardiac fibroblasts, which showed reduced glycolysis, altered lipid handling, and increased glutamine metabolism, promoting cytosolic acetyl-CoA production via ACLY in the early phase. This shift may drive sustained fibroblast activation in the long-term, through post-translational and epigenetic mechanisms, contributing to cardiotoxicity via metabolic crosstalk with cardiomyocytes and induction of senescence. Conclusions Overall, this work demonstrates that DOX induces an acute increase in metabolic activity, with a reprogramming of different cardiac cells metabolism. While initially adaptive, this response becomes maladaptive over time, ultimately leading to chronic cardiac dysfunction.
Guerra et al. (Sun,) reported a other. Doxorubicin induces an acute hypermetabolic state in cardiac cells that progresses to maladaptation and chronic dysfunction, mitigated by targeting the PI3Kγ–PDK4–PDH axis.