Bax is essential for Drp1‐mediated mitochondrial fission but not for mitochondrial outer membrane permeabilization caused by photodynamic therapy

Abstract

Bcl-2 family proteins are critical for the regulation of apoptosis, with the pro-apoptotic members Bax essential for the release of cytochrome c from mitochondria in many instances. However, we found that Bax was activated after mitochondrial depolarization and the completion of cytochrome c release induced by photodynamic therapy (PDT) with the photosensitizer Photofrin in human lung adenocarcinoma cells (ASTC-a-1). Besides, knockdown of Bax expression by gene silencing had no effect on mitochondrial depolarization and cytochrome c release, indicating that Bax makes no contribution to mitochondrial outer membrane permeabilization (MOMP) following PDT. Further study revealed that Bax knockdown only slowed down the speed of cell death induced by PDT, indicating that Bax is not essential for PDT-induced apoptosis. The fact that Bax knockdown totally inhibited the mitochondrial accumulation of dynamin-related protein (Drp1) and Drp1 knockdown attenuated cell apoptosis suggest that Bax can promote PDT-induced apoptosis through promoting Drp1 activation. Besides, Drp1 knockdown also failed to inhibit PDT-induced cell death finally, indicating that Bax-mediated Drp1's mitochondrial translocation is not essential for PDT-induced cell apoptosis. On the other hand, we found that protein kinase Cδ (PKCδ), Bim L and glycogen synthase kinase 3β (GSK3β) were activated upon PDT treatment and might contribute to the activation of Bax under the condition. Taken together, Bax activation is not essential for MOMP but essential for Drp1-mediated mitochondrial fission during the apoptosis caused by Photofrin-PDT.

Cell Death Pathways in Photodynamic Therapy of Cancer

“…The dependence of Pc4-PDT induced apoptosis on Bax remains under active investigation and reports from Chiu et al [60,61] indicated that commitment to cell death after PDT occurs prior to Bax activation while Usuada et al [62] reported that Smac/DIABLO promotes apoptosis after Pc4-PDT in a Bax dependent manner. Furthermore, Bax was not found to be essential for Photofrin-PDT induced apoptosis in human lung adenocarcinoma cells (ASTC-a-1) [63]. In the absence of Bax/Bak, autophagy appears to be predominantly responsible for cell death following PDT with different photosensitizers [64-66].…”

Multiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis

“…In contrast, Bax-induced mitochondrial fragmentation is required for the release of cytochrome c, but failed to block mitochondrial fission that is associated with Bax/Bak activation. This suggests that Bax/Bak-initiated remodeling of mitochondrial networks and cytochrome c release is separate events and that the proteins in the Bcl-2 family influence mitochondrial fission-fusion dynamics, independent of apoptosis [82–83]. Interestingly, cristae remodeling also plays an important role in cytochrome c release during intrinsic apoptosis.…”

Cancer PhototherapyviaSelective Photoinactivation of Respiratory Chain Oxidase to Trigger a Fatal Superoxide Anion Burst

“…Our previous study showed that either HF-LPLI or photodynamic therapy (PDT) could induce cell apoptosis via the mitochondrial pathway by triggering the generation of ROS (41,42). To confirm the damage effect of ROS generated by HF-LPLI, we studied the correlation between ROS generation and mitochondrial injury in human lung adenocarcinoma cell line (ASTC-a-1) cells (Fig.…”