Cigarette smoke is one of major risk factors in the pathogenesis of chronic obstructive pulmonary disease (COPD). It is generally believed that cigarette smoke induces mitochondrial damage in the alveolar epithelial cells to contribute to COPD. However, the exact molecular mechanism remains unknown for the mitochondrial damage. In this study, cigarette smoke extract (CSE) was found to induce the mitochondrial membrane permeability (MMP), which promoted proton leakage leading to the reduction in mitochondrial potential and ATP production. ANT in the mitochondrial inner membrane was activated by CSE for the alteration of MMP. The activation was observed without an alteration in the protein level of ANT. Inhibition of the ANT activity with ADP or bongkrekic acid prevented the MMP alteration and potential drop upon CSE exposure. The ANT activation was observed with a rise in ROS production, inhibition of the mitochondrial respiration, decrease in the complex III protein and rise in mitophagy activity. The results suggest that ANT may mediate the toxic effect of cigarette smoke on mitochondria and control of ANT activity is a potential strategy in intervention of the toxicity.

Dexamethasone (Dex) causes osteoblast cell injuries. In the present research, we tested the potential effect of SC79, a novel and specific Akt activator, against Dex in osteoblasts. In primary murine osteoblasts and osteoblastic MC3T3-E1 cells, pretreatment with SC79 significantly attenuated Dex-induced cell death. Further, Dex-induced mitochondrial permeability transition pore (mPTP) opening, cytochrome C release and apoptosis activation were dramatically alleviated with SC79 pretreatment in above cells. At the molecular level, SC79 activated Akt, which was indispensable for subsequent osteoblast protection against Dex. Akt inhibitors (LY294002, perifosine and MK-2206) blocked SC79-induced Akt activation and abolished its anti-Dex actions in osteoblasts. Further, SC79 activated Akt downstream Nrf2 (NF-E2-related factor 2) signaling and attenuated Dex-induced oxidative stress in osteoblasts. Nrf2 shRNA knockdown or S40T mutation almost reversed SC79-mediated anti-oxidant and cytoprotective activities in osteoblasts. Together, these results suggest that SC79 activates Akt-Nrf2 signaling to protect osteoblasts from Dex.

Induction of apoptosis is a strategy in the treatment of glioma, a malignant tumor with the highest prevalence in the brain. Sodium butyrate (NaB) induces apoptosis in glioma cells at pharmacological dosages (>2.5 mM), but the mechanism remains largely unknown beyond the mitochondrial potential drop. In this study, NaB was found to open the mitochondrial permeability transient pore (MPTP) to induce a proton leak in the mechanism of apoptosis. The MPTP opening led to collapse of mitochondrial potential and suppression of ATP production in the NaB-treated cells. Proton leak was increased in the mitochondria under the coupling and uncoupling conditions from the MPTP opening. The proton leak was associated with an elevation in the protein abundance of adenine nucleotide translocator 2 (ANT2) and was blocked by an ANT-specific inhibitor of bongkrekic acid (BA). These data suggest that the proton leak is induced by NaB for the mitochondrial potential drop in the induction of apoptosis. The mechanism may be related to activation of ANT2 in the MPTP complex.