Mitochondria plays a fundamental role in regulating cell function.
Although cancer cells relatively have nothing to do with ATP-producing mitochondrial oxidation pathway, mitochondria are still decisive in regulating cellular homeostasis and cell death (Hsu, Tseng et al. 2016, Vyas, Zaganjor et al. 2016). Rapid morphological changes happen in mitochondrial fission and fusion as a response to physiological and pathological conditions (Chen and Chan 2005, Ussakli, Ebaee et al. 2013, Srinivasan, Guha et al. 2017).
Mitochondrial kinetic dysfunction is associated with many neurodegenerative diseases, supporting the role of fission and nuclear fusion in maintaining cell homeostasis(Caino and Altieri 2016, Iommarini, Ghelli et al. 2017, Srinivasan, Guha et al. 2017). We observed that ALA-SDT can reduce mitochondrial membrane potential and ATP production, which means mitochondrial dysfunction has happened (Caino and Altieri 2016, Iommarini, Ghelli et al.
2017, Srinivasan, Guha et al. 2017). And the mitochondrial rupture caused by mitochondrial division is also triggered by ALA-SDT. We also found that the expression of mitochondrial fission protein FISF1 increased as the morphology of mitochondria changed from tubular, to punctiform, to mitochondrial fragmentation, while expression of mitochondrial fusion
46
protein MFN1 decreased. In conclusion, ALA-SDT induces mitochondrial dysfunction and leads to more fragmented mitochondria through fission.
As is known to all, mitophagy serves as a vital protective mechanism that selectively removes damaged mitochondria and maintains normal functional status of mitochondria to meet metabolic needs. Mitophagy can be triggered by dysfunctional mitochondria (Kubli and Gustafsson 2012, Kurihara, Kanki et al. 2012). The most complete documented signaling pathway controlling mitophagy is the PINK 1-Parkin pathway. PINK 1 or Parkin mutations cause mitochondrial dysfunction and are directly related with Parkinson's disease (de Vries and Przedborski 2013, Ryan, Hoek et al.
2015). In this study, the co-localization of mitochondria and autophagosome/lysosome was significantly increased; The expression of PINK1 was increased; Parkin was transferred from it. From cytoplasm to mitochondria, ALA-SDT induced mitochondrial autophagy in cultured MCF-7 cells and was engaged in the activation of the PINK 1-Parkin signaling pathway. Therefore, the PINK 1-Parkin pathway is a key to maintaining a healthy mitochondrial population by promoting mitophagy.
47
It has been reported that there exists an intricate crosstalk between mitophagy, apoptosis and cell death (Gump and Thorburn 2011, Zhang 2013).
Normally, mitophagy should be protective in response to mitochondrial injury and damaged mitochondria. But in some cases, excessive mitophagy may leads to excessive degradation of the mitochondria, which ultimately leads to irreversible cell death - autophagic cell death (Kim, Rodriguez-Enriquez et al.
2007, Green and Levine 2014). Our study showed that Parkin knockdown lower cell viability and higher apoptosis rate, suggesting that ALA-SDT plays a protective role of mitophagy. This means that mitochondrial autophagy has an undiscovered function in regulating the sensitivity of SDT to kill the tumor.
And drugs designed for mitochondrial autophagy can promote ALA-SDT to be more efficient.
Many studies have illustrated how ROS works in pathological conditions and how apoptosis was initiate by it (Ling, Liebes et al. 2003, Di Meo, Reed et al. 2016). ROS mainly target at mitochondria, which are considered to provide most of ROS within the cell (Mao, Yu et al. 2008, Schieber and Chandel 2014). We show that ALA-SDT induced significant accumulation in cellular and mitochondrial ROS, and increased expression of cellular proteins and mitochondrial antioxidant. Antioxidant imbalance - which means that oxidation will occur after ALA-SDT. ROS has been shown
48
to cause activation of multiple signaling pathways, mitochondrial dysfunction, and induction of mitophagy. In this study, the ROS inhibitor NAC was used to reduce intracellular and mitochondrial pro-apoptotic functions and explore its role in apoptosis of SDT cells. NAC significantly inhibited ALA-SDT induced mitochondrial membrane potential and ATP production. At the same time, ALA-SDT-induced mitophagy decreased significantly after the NAC treatment. These results indicate that ALA-SDT-induced ROS formation is an important intracellular factor that triggers mitophagy. In this article, we demonstrate that ALA-SDT mediates the production of excess ROS that can make mitochondrial dysfunction and lead to mitophagy. We have also found, PINK 1-Parkin signal pathway involved in ALA-SDT mediated mitophagy protects the cell viability and mitochondrial function under oxidative stress.
49
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