Mitophagy is a selective autophagic process which leads to

Mitophagy is a selective autophagic process which leads to the degradation of damaged mitochondria in response to metabolic or environmental stress conditions. In this study, we found that LFS-01 treatment significantly enhances p62 in a time-dependent manner. We found that the upregulation of p62 is due to the modulation of CRM1 and subsequent nuclear accumulation of cargo protein Nrf2, a transcription factor that triggers and regulates p62 expression [40,41]. Our results are in line with prior reports that p62, an autophagic adaptor, is indispensable for the clearance of defective mitochondria during mitophagic events [42]. Namely, the accumulation of p62 is closely associated with the induction of mitophagic signaling. Noteworthy, our study is the first to establish the functional link between CRM1-mediated upregulation of p62 and mitophagic cellular death in tumor cells. In addition, we found that nuclear p53 of lymphoma orphan receptor were increased in dose-dependent manner after LFS-01 treatment. Despite the well-documented role of p53 as a tumor suppressor, accumulating evidence suggest that p53 present in cytoplasmic compartment can suppress mitophagy. Therefore, we want to argue that nuclear accumulation of p53 caused by LFS-01 treatment may counteract the suppressing effects of cytoplasmic p53 towards mitophagy. More importantly, we showed that AMPK, a primary inducer of mitophagy in response to mitochondria stress, was activated upon LFS-01 exposure. This is in accordance with recent findings that the activation of AMPK is directly associated with mitochondria fission followed by mitophagy events [8]. Furthermore, we demonstrated that mTOR, a central signal integrator and a negative regulator of mitophagy, was inactivated upon LFS-01 treatment. This is consistent with previous research that activation of AMPK can lead to inhibition of mTOR and induction of mitophagic signaling. Collectively, our results demonstrated that concomitant mitophagy and apoptosis are crucial mechanisms accounting for the selective killing of lymphoma cells by LFS-01 through the CRM1-mediated overexpression of p62 and engagement of AMPK/mTOR pathway. The functional crosstalk between autophagy (including mitophagy) and apoptosis remains as a topic of much debate. In some scenarios, autophagy or mitophagy plays a protective role for cells in response to a stress or stimuli whereas in other cellular settings, autophagy or mitophagy constitutes an alternative or synergistic pathway leading to cellular demise [43]. The induction of autophagic or mitophagic cell death could be particularly useful and may constitute a ‘fail safe’ mechanism when the cellular death by apoptosis is inefficient or defective. Hence, therapeutics that can trigger both mitophagy and apoptosis may represent a very attractive approach for selective and efficient killing of tumor cells, as several studies have suggested [44,45]. To this end, our study reported a naturally-derived compound that enables a functional cooperation and synergistic effects between mitophagy and apoptosis for the efficacious killing of liquid tumor cells.
Conclusions
Compliance with ethical standards Disclosure of potential conflicts of interest: Lei Mao serves as Chief Computing Officer for DrivingForce Therapeutics (DFT); Yongliang Yang is a scientific co-Founder of DFT and Cheng Li is a scientific advisor to DFT. Research involving human participants and/or animals: All applicable international, national, and/or institutional guidelines for the care and use of animals were followed; All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study.
Author contributions
Acknowledgments