Cisplatin chemotherapy often causes acute kidney injury (AKI) in cancer patients. There is increasing evidence that mitochondrial dysfunction plays an important role in cisplatin-induced nephrotoxicity. Degradation of damaged mitochondria is carried out by mitophagy. Although mitophagy is considered of particular importance in protecting against AKI, little is known of the precise role of mitophagy and its molecular mechanisms during cisplatin-induced nephrotoxicity. Also, evidence that activation of mitophagy improved mitochondrial function is lacking. Furthermore, several evidences have shown that mitochondrial fission coordinates with mitophagy. The aim of this study was to investigate whether activation of mitophagy protects against mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. The effect of mitochondrial fission on mitophagy was also investigated. In cultured human renal proximal tubular cells, we observed that 3-methyladenine, a pharmacological inhibitor of autophagy, blocked mitophagy and exacerbated cisplatin-induced mitochondrial dysfunction and cells injury. In contrast, autophagy activator rapamycin enhanced mitophagy and protected against the harmful effects of cisplatin on mitochondrial function and cells viability. Suppression of mitochondrial fission by knockdown of its main regulator dynamin-related protein-1 (Drp1) decreased cisplatin-induced mitophagy. Meanwhile, Drp1 suppression protected against cisplatin-induced cells injury by inhibiting mitochondrial dysfunction. Our results provide evidence that Drp1-depedent mitophagy has potential as renoprotective targets for the treatment of cisplatin-induced AKI.
Mitochondrial dysfunction is increasingly recognized as an important factor in glomerular diseases. Previous study has shown that mitochondrial fission contributed to mitochondrial dysfunction. However, the mechanism of mitochondrial fission on mitochondrial dysfunction in aldosterone-induced podocyte injury remains ambiguous. This study aimed to investigate the pathogenic effect of mitochondrial fission both in vivo and in vitro. In an animal model of aldosterone-induced nephropathy, inhibition of the mitochondrial fission protein dynamin-related protein 1 (Drp1) suppressed aldosterone-induced podocyte injury. In cultured podocytes, aldosterone dose dependently induced Drp1 expression. Knockdown of Drp1 inhibited aldosterone-induced mitochondrial fission, mitochondrial dysfunction, and podocyte apoptosis. Furthermore, aldosterone dose dependently induced p53 expression. Knockdown of p53 inhibited aldosterone-induced Drp1 expression, mitochondrial dysfunction, and podocyte apoptosis. These findings implicated that aldosterone induced mitochondrial dysfunction and podocyte injury mediated by p53/Drp1-dependent mitochondrial fission, which may provide opportunities for therapeutic intervention for podocyte injury.
In permanent-magnet synchronous machine (PMSM) applications, traditional deadbeat predictive current control (DPCC) utilizes the PMSM model to evaluate the expected voltage vector and applies it to the inverter through space vector pulse width modulation (SVPWM). Once the expected voltage vector is inaccurate, the torque ripple and speed fluctuation are amplified. There are two main factors that cause the inaccurate voltage vector, namely model parameter mismatch, and current measurement error. To enhance the robustness of DPCC, first, this paper proposes an accurate PMSM voltage model with nonperiodic and periodic disturbance models. Second, this paper proposes a novel current and disturbance observer (NCDO) which is able to predict future stator currents and disturbances caused by model parameter mismatch and current measurement error simultaneously. Finally, the scheme of the proposed DPCC with NCDO is presented to enhance the robustness. This paper presents a comparative study of two types of algorithms, namely traditional DPCC and the proposed DPCC with NCDO. The theoretical verification, simulation results, and experimental results are demonstrated to verify the effectiveness of the proposed DPCC with NCDO.INDEX TERMS Permanent-magnet synchronous machine (PMSM), deadbeat predictive current control (DPCC), iterative learning control (ILC), sliding-mode control (SMC).
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