Targeted cytoplasmic irradiation and autophagy

Abstract

The effect of ionizing irradiation on cytoplasmic organelles is often underestimated because the general dogma considers direct DNA damage in the nuclei to be the primary cause of radiation induced toxicity. Using a precision microbeam irradiator, we examined the changes in mitochondrial dynamics and functions triggered by targeted cytoplasmic irradiation with α-particles. Mitochondrial dysfunction induced by targeted cytoplasmic irradiation led to activation of autophagy, which degraded dysfunctional mitochondria in order to maintain cellular energy homeostasis. The activation of autophagy was cytoplasmic irradiation-specific and was not detected in nuclear irradiated cells. This autophagic process was oxyradical-dependent and required the activity of the mitochondrial fission protein dynamin related protein 1 (DRP1). The resultant mitochondrial fission induced phosphorylation of AMP activated protein kinase (AMPK) which leads to further activation of the extracellular signal-related kinase (ERK) 1/2 with concomitant inhibition of the mammalian target of rapamycin (mTOR) to initiate autophagy. Inhibition of autophagy resulted in delayed DNA damage repair and decreased cell viability, which supports the cytoprotective function of autophagy. Our results reveal a novel mechanism in which dysfunctional mitochondria are degraded by autophagy in an attempt to protect cells from toxic effects of targeted cytoplasmic radiation.

Tetramethylpyrazine Prevents Contrast-Induced Nephropathy via Modulating Tubular Cell Mitophagy and Suppressing Mitochondrial Fragmentation, CCL2/CCR2-Mediated Inflammation, and Intestinal Injury

“…Based on the present data, TMP appeared to suppress renal ROS production and protect tubular cells against CM cytotoxicity via decreased mitophagy, autophagy, and apoptosis. There is increasing evidence to suggest that overproduction of mitochondrial ROS leads to an increase in mitochondrial fragmentation that results in tubular cell damage and apoptosis in diabetic kidney disease (DKD) [12]. Our present data are highly consistent with these findings in DKD.…”

“…Thus, we speculated that although the roles of mitophagy induction and mitochondrial fragmentation in CIN remain unknown, mitophagy may be involved in the pathogenesis of CIN. Previous work from our laboratory has shown that autophagy requires the activity of the protein Drp1 [12, 13], which was used as a marker of autophagy in this study.…”

Nuclear factor (erythroid‐derived 2)‐like 2 antioxidative response mitigates cytoplasmic radiation‐induced DNA double‐strand breaks

“…Mitochondrial fragmentation was observed in our research in cytoplasm‐irradiated cells, in line with the findings of Zhang et al . Furthermore, Wu et al found that the mitochondrial fragmentation inhibitor Mdivi‐1 could block cytoplasmic irradiation‐induced autophagy in SAE cells, and autophagy inhibition delayed the repair of cytoplasmic irradiation‐induced DSB . Overall, our results provided another mechanism for the protective role of mitochondrial fragmentation in decreasing cytoplasmic irradiation‐induced DSB level.…”

Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1

“…7A). Although a mechanistic association between mitochondrial dynamics and mTORC1 has not been explored in depth, it is noteworthy that a potential link was recently reported between mitochondrial fission and mTORC1-mediated regulation of autophagy in cells exposed to ionizing radiation-induced stress (Wu et al, 2017). …”