SOD1 and MitoTEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery

Abstract

Generation of excessive reactive oxygen species (ROS) leads to mitochondrial dysfunction, apoptosis and necrosis in renal ischemia-reperfusion (IR) injury. Previously we showed that lentiviral vector mediated over-expression of superoxide dismutase-1 (SOD1) in proximal tubular epithelial cells (LLC-PK 1 ) reduced cytotoxicity in an in vitro model of IR injury. Here, we examined the effects of SOD1 over-expression on mitochondrial signaling following ATP depletion-recovery (ATP-DR). To examine the role of mitochondrial ROS, a subset of cells were treated with the mitochondrial antioxidant, MitoTEMPO. ATP-DR-mediated increases in mitochondrial calcium ([Ca 2+ ] m ), loss of mitochondrial membrane potential (ΔΨ m ) and increase in mitochondrial permeability transition pore (MPTP) were attenuated by SOD1 and MitoTEMPO (P < 0.01). SOD1 prevented ATP-DR induced mitochondrial Bax translocation, although the release of pro-apoptotic proteins from mitochondria was not prevented by SOD1 alone and required the presence of both SOD1 and MitoTEMPO. SOD1 suppressed the increase in c-jun phosphorylation suggesting that JNK signaling regulates Bax translocation to mitochondria via ROS. ATP-DRmediated changes in MPTP and mitochondrial signaling increased necrosis and apoptosis, both of which were partially attenuated by SOD1 and MitoTEMPO. These studies show that SOD1 and MitoTEMPO preserve mitochondrial integrity and attenuate ATP-DR mediated necrosis and apoptosis.

Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death

“…Modulation of mitochondrial Ca 2+ uptake or release alters oxidation within hair cells exposed to aminoglycosides in a manner consistent with their central involvement in the process. Furthermore, aminoglycoside protection afforded by mitoTEMPO lies in stark contrast to that of TEMPOL despite the ability of both compounds to act as electron sinks (65)(66)(67).…”

SSBP1 Suppresses TGFβ-Driven Epithelial-to-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer by Regulating Mitochondrial Retrograde Signaling

“…Western blot and immunofluorescence assays demonstrated that SSBP1 deficiency resulted in lower E-cadherin expression and higher N-cadherin and fibronectin expression. Of note, treatment with GW788388 and MitoTEMPO, an inhibitor of TGFb/SMAD3 signaling and mitochondrial ROS, respectively (26)(27)(28), mitigated the effects of SSBP1 deficiency on the cell invasive ability and EMT (Fig. 5D-G).…”

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments

“…Antioxidants such as NAC, Mito-TEMPO, and SOD have also been observed to alleviate mitochondrial fragmentation and apoptosis, as well as reduce cellular senescence and the opening of mitochondrial permeability transition pores (45,73). Although the use of antioxidants in the treatment of COPD is limited, investigations underlying the therapeutic index of radical-scavenging pharmaceuticals are currently underway.…”