Autophagy protein Ulk1 promotes mitochondrial apoptosis through reactive oxygen species |
| |
| Institution: | 1. Department of Life Science, National Institute of Technology, Rourkela, Odisha, India;2. Department of Biotechnology & Medical Engineering, National Institute of Technology, Rourkela, Odisha, India;1. Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;2. Pulmonary Injury and Repair Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA;3. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294,USA;4. Center for Free Radical Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;5. Veterans Administration Medical Center, Birmingham, AL 35233, USA;1. Nuffield Department of Obstetrics and Gynaecology, Women’s Centre, Oxford, UK;2. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK;3. Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK;4. Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney and Royal North Shore Hospital, Sydney, Australia;5. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK;6. Department of Mathematics, Imperial College London, London, UK;7. Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK;8. Department of Neuroscience, Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, UK;1. Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada;2. Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt;3. Canadian Rivers Institute, Department of Biology, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada |
| |
| Abstract: | Regardless of rapid progression in the field of autophagy, it remains a challenging task to understand the cross talk with apoptosis. In this study, we overexpressed Ulk1 in HeLa cells and evaluated the apoptosis-inducing potential of the Ulk1 gene in the presence of cisplatin. The gain of function of Ulk1 gene showed a decline in cell viability and colony formation in HeLa cells. The Ulk1-overexpressing cells showed higher apoptotic attributes by an increase in the percentage of annexin V, escalated expression of Bax/Bcl2 ratio, and caspase-9, -3/7 activities. Further, reactive oxygen species (ROS) generation was found to be much higher in HeLa-Ulk1 than in the mock group. Scavenging the ROS by N-acetyl-L-cysteine increased cell viability and colony number as well as mitochondrial membrane potential (MMP). Our data showed that Ulk1 on entering into mitochondria inhibits the manganese dismutase activity and intensifies the mitochondrial superoxide level. The Ulk1-triggered autophagy (particularly mitophagy) resulted in a fall in ATP; thus the nonmitophagic mitochondria overwork the electron-transport cycle to replenish energy demand and are inadvertently involved in ROS overproduction that led to apoptosis. In this present investigation, our results decipher a previously unrecognized perspective of apoptosis induction by a key autophagy protein Ulk1 that may contribute to identification of its tumor-suppressor properties through dissecting the connection among cellular bioenergetics, ROS, and MMP. |
| |
| Keywords: | Ulk1 Apoptosis Autophagy Mitochondrial superoxide dismutase Reactive oxygen species ATP depletion |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
