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Recent studies have shown that FMS-like receptor tyrosine kinase 3 (Flt3) has a beneficial effect on cardiac maladaptive remodeling. However, the role and mechanism of Flt3 in mitochondrial dynamic imbalance under cardiac stress remains poorly understood. This study aims to investigate how Flt3 regulates p53-mediated optic atrophy 1 (OPA1) processing and mitochondrial fragmentation to improve cardiac remodeling. Mitochondrial fragmentation in cardiomyocytes was induced by isoprenaline (ISO) and H2O2 challenge, respectively, in vitro. Cardiac remodeling in mice was established by ligating the left anterior descending coronary artery or by chronic ISO challenge, respectively, in vivo. Our results demonstrated that the protein expression of acetylated-p53 (ac-p53) in mitochondria was significantly increased under cell stress conditions, facilitating the dissociation of PHB2-OPA1 complex by binding to prohibitin 2 (PHB2), a molecular chaperone that stabilizes OPA1 in mitochondria. This led to the degradation of the long isoform of OPA1 (L-OPA1) that facilitates mitochondrial fusion and resultant mitochondrial network fragmentation. This effect was abolished by a p53 K371R mutant that failed to bind to PHB2 and impeded the formation of the ac-p53-PHB2 complex. The activation of Flt3 significantly reduced ac-p53 expression in mitochondria via SIRT1, thereby hindering the formation of the ac-p53-PHB2 complex and potentiating the stability of the PHB2-OPA1 complex. This ultimately inhibits L-OPA1 processing and leads to the balancing of mitochondrial dynamics. These findings highlight a novel mechanism by which Flt3 activation mitigates mitochondrial fragmentation and dysfunction through the reduction of L-OPA1 processing by dampening the interaction between ac-p53 and PHB2 in cardiac maladaptive remodeling.

The polymerization of N,N'-diethylacrylamide (DEA) into PDEA hydrogels could be initiated by glucose oxidase (GOD) in the presence of glucose, Fe2+ and oxygen. Based on this, the semi-interpenetrating polymer network (semi-IPN) films containing PDEA, hyaluronic acid (HA) and GOD were prepared on electrode surface. The electroactive probe ferrocenedicarboxylic acid (Fc(COOH)2) in solution demonstrated reversible pH-, temperature- and SO42--sensitive cyclic voltammetric (CV) on-off behavior at the film electrodes. Taking pH-responsive property of the system as an example, at pH 4.5, the probe showed a large and well-defined CV peak pair, and the system was at the on state; while at pH 8.0, the CV peaks were greatly suppressed and the system was at the off state. The system could be further used to switch the electrochemical oxidation of glucose catalyzed by GOD in the films and mediated by Fc(COOH)2 in solution with pH, temperature and SO42- as the stimuli. Herein the enzyme GOD functioned in two ways: (1) in preparation of the films, GOD could induce radical polymerization of PDEA; (2) in the following electrochemical studies, GOD could catalyze the oxidation of glucose and helped to realize the switchable bioelectrocatalysis with amplification effect. [ABSTRACT FROM AUTHOR]