Phosphoinositide 3-kinase gamma at the crossroad between autophagy and metabolic control in doxorubicin-induced cardiomyopathy
Presented by: Emilio Hirsch
Presentation time:
Purpose: Doxorubicin (DOX) is a highly effective chemotherapeutic for the treatment of hematopoietic malignancies and solid tumours. However, the clinical use of DOX in cancer patients is hampered by dose-dependent cardiotoxicity occurring within one year from treatment completion. Effective cardioprotective strategies to prevent DOX toxicity are still missing mainly because of an incomplete understanding of the underlying molecular mechanisms. We previously described that phosphoinositide 3-kinase γ (PI3Kγ) promotes DOX-induced cardiomyopathy by inhibiting mitochondrial autophagy and that pharmacological or genetic inhibition PI3Kγ restores autophagic disposal of damaged mitochondria and promotes cardioprotection. Here we sought to investigate how and to what extent this mechanism affects cardiac metabolism.
Methods: Wild-type (WT) and knock-in mice expressing a kinase-inactive PI3Kγ (PI3Kγ kinase-dead; KD) were treated i.p. with DOX weekly for 3 weeks (4 mg/Kg on day 0, 7 and 14, cumulative dose 12 mg/Kg). Activity of glycolytic enzymes, mitochondria respiration rate, ketone bodies and glutamine consumption were measured in whole hearts at 3 and 42 days after the first DOX injection. To investigate the involvement of autophagy, WT and KD mice were injected with DOX (4 mg/Kg) on day 0 and with bafilomycin (0.3 mg/Kg on day 0, 1 and 2). Mice were sacrificed at day 3 and hearts were used for metabolic analysis as above.
Results: Fatty Acid Oxidation capacity and Electron Transport Chain activity was compromised in WT+DOX mice, resulting in an increase of ROS formation. Mitochondria dysfunction was associated with upregulation of glycolysis activity and reduction of ATP production. These effects were prevented in KD+DOX mice, that showed an increase of ketone bodies consumption and intracellular content of glutamine. Inhibition of autophagy abolished cardioprotective effect in KD+DOX mice and, interestingly, abrogates glucose utilization in both WT+DOX and KD+DOX groups.
Conclusion: Overall, these results demonstrate that DOX promotes a metabolic rewiring of cardiomyocytes towards increased glucose utilization and identifies PI3Kγ as a master regulator of this metabolic switch.
Methods: Wild-type (WT) and knock-in mice expressing a kinase-inactive PI3Kγ (PI3Kγ kinase-dead; KD) were treated i.p. with DOX weekly for 3 weeks (4 mg/Kg on day 0, 7 and 14, cumulative dose 12 mg/Kg). Activity of glycolytic enzymes, mitochondria respiration rate, ketone bodies and glutamine consumption were measured in whole hearts at 3 and 42 days after the first DOX injection. To investigate the involvement of autophagy, WT and KD mice were injected with DOX (4 mg/Kg) on day 0 and with bafilomycin (0.3 mg/Kg on day 0, 1 and 2). Mice were sacrificed at day 3 and hearts were used for metabolic analysis as above.
Results: Fatty Acid Oxidation capacity and Electron Transport Chain activity was compromised in WT+DOX mice, resulting in an increase of ROS formation. Mitochondria dysfunction was associated with upregulation of glycolysis activity and reduction of ATP production. These effects were prevented in KD+DOX mice, that showed an increase of ketone bodies consumption and intracellular content of glutamine. Inhibition of autophagy abolished cardioprotective effect in KD+DOX mice and, interestingly, abrogates glucose utilization in both WT+DOX and KD+DOX groups.
Conclusion: Overall, these results demonstrate that DOX promotes a metabolic rewiring of cardiomyocytes towards increased glucose utilization and identifies PI3Kγ as a master regulator of this metabolic switch.