PhD, National University of Singapore, Singapore, 2002
Postdoctoral Fellowship, University of Pittsburgh, 2005
Autophagy and Apoptosis in liver injury and cancer therapy; Redox Signaling and Mitochondrial damage; Mitophagy
Autophagy and Apoptosis in liver injury and cancer therapy; Redox Signaling and Mitochondrial damage; Mitophagy
1. Mechanisms of autophagy in alcoholic liver disease.
Macroautophagy (referred to as autophagy hereafter) is a major intracellular degradation system that is responsible for the degradation of long-lived proteins and other cellular contents. It is usually activated in response to adverse environment, such as the deprivation of nutrients or growth factors. Autophagy plays a role in development, in defending against microbial infections, in regulating lipid homeostasis and organelles turn over such as mitochondria, and in the pathogenesis of a number of diseases including cancer.
Alcohol abuse is a major cause of liver injury. The pathology of alcoholic liver disease develops over a prolonged period. However, the cellular defense mechanisms against the detrimental effects of alcohol are not well understood. We recently demonstrated that autophagy is activated and protects against acute ethanol-induced liver injury and steatosis in mice. Specifically, we found that ethanol-induced autophagy may selectively remove damaged mitochondria (mitophagy) and lipid droplets (lipophagy). The research work in this laboratory is to study the mechanisms by which ethanol induces autophagy and to explore potential therapeutic drugs for alcoholic diseases by inducing autophagy. We are also interested in studying how autophagy would help to reduce alcohol-induced fatty liver (steatosis) and non-alcoholic fatty liver (NASH). Furthermore, we would also apply our autophagy liver model to other drug-induced and bile acids-induced liver injury models.
Ethanol induces mitophagy in mouse hepatocytes. (A) Confocal microscopy images of ethanol-treated mouse hepatocytes (green: GFP-LC3; Red: Mitotracker red). (B) Electron microscopy images of ethanol-treated mouse hepatocytes. Be noted double membrane enveloped mitochondria.
Ding et al., Gastroenterology 2010; Ding et al., EBM 2011; Ni et al Pharm Res. 2012; Ni et al AJP 2013; Williams et al., WJG 2014, Li Y et al., BioMedical Research International 2014
ROS: reactive oxygen species, ADH: alcohol dehydrogenase, LD: lipid droplets
2. Mechanisms of mitochondria autophagy (mitophagy)
Mitochondria are dynamic organelles that are responsible for creating more than 90% of the energy needed by the body. Mitochondria are also the central-regulators for apoptosis and the major sources for the production of reactive oxygen species. Many environmental toxicants and chemotherapeutic drugs can damage mitochondria. Damaged mitochondria have been involved in cell death, ischemia and reperfusion injury, aging and many neurodegenerative conditions such as Alzheimer's and Parkinson's disease. It is thus important to eliminate damaged and aged mitochondria to protect the cells against its detrimental effects on the cells. It is now known that autophagy plays an important role to remove these damaged mitochondria, a process, called mitophagy. However, it is not known how damaged mitochondria are eventually recognized by the autophagosomes in mammalian cells although it has recently been reported that Atg32 is required for mitophagy in yeast. We and others recently found that Parkin, an E3 ligase which is commonly mutated in Parkinson's disease, promotes damaged mitochondria ubiquitination and p62 targeting and subsequent mitophagy. Our current research work is to study the molecular signals that could be involved in this process such as redox signaling and mitochondrial fission and fusion machinery. We are also using Parkin knockout mice to investigate the role of Parkin in mitophagy in vivo.
CCCP induces Parkin-mediated mitophagy. Hela cells were transfected with mCherry parkin and treated with CCCP for 6 hrs.
Ding et al., JBC 2010
Ding et al., JBC 2012; Ding et al Biol Chem. 2012
3. Targeting autophagy for drug-induced liver injury.
The liver is a vital organ that has a wide range of functions. One of the major functions of the liver is to metabolize and detoxify drugs. Consequently, liver is also often the major target to be damaged by drugs. Drug-induced liver injury is one of the most frequent reasons for the withdrawal of an approved drug from the market, and it accounts for up to 50% of acute liver failure cases. Acetaminophen (APAP) is a safe drug at therapeutic levels, but an overdose can cause severe liver injury in animals and man. We recently demonstrated that pharmacological induction of autophagy significantly inhibits APAP-induced liver injury in mouse by removing APAP-induced damaged mitochondria, a process called mitophagy. Induction of mitophagy can attenuate APAP-induced mitochondrial-mediated oxidative stress. We are currently investigating how autophagy specifically removes APAP-induced damaged mitochondria by focusing on Parkin, an E3 ubiquitin ligase, and other targets. With the rapid progress in the discovery of autophagy inducers rather than rapamycin, targeting autophagy could be a novel avenue for treating the APAP overdose patients.
Ni et al., Hepatology 2012; Ni et al., Autophagy, 2012; Ni et al., Toxi Sciences 2012; Ni et al., Pharm. Res. 2012; Ni et al., Redox Biology 2013
4. SQSTM1/p62 mediated-Nrf2 activation promotes liver injury and tumorigenesis in Atg5 liver-specific knockout mice
Autophagy-deficient livers have increased accumulation of p62/SQSTM1, an autophagy substrate and receptor protein. p62 competes with Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) for binding to Keap1 (Kelch-like ECH-associated protein 1) resulting in dissociation of Nrf2 from Keap1 and activation of Nrf2, a transcription factor which regulates expression of cytoprotective genes and hepatic detoxification enzymes. Accumulation of p62 and activation of Nrf2 have been found in human HCCs. Interestingly, we recently demonstrated that p62/SQSTM1-mediated Nrf2 activation is the detrimental factor for the loss of hepatocyte Atg5-induced liver injury, fibrosis and eventual tumorigenesis. Ongoing work is aimed to determine how Nrf2, a traditional thought "good transcriptional factor" for antioxidant genes protecting against oxidative stress, actually cause cell death and tumorigenesis in Atg5-deficient liver.
Selected Publications (recent 5 years since joined KUMC 2009)
Ding, W.X., Ni, H.M., Liao, Y., Li, M., Gao, W., Stolz, D.B., Gerald, W.D.II. and Yin, X.M. (2010) Nix is critical to two distinct phases of mitophagy: reactive oxygen species (ROS)-mediated autophagy induction and Parkin-ubiqutin- p62-mediated mitochondria priming. J Biol Chem. 3;285(36):27879-90. PMID: 20573959.
Ding, W.X. Li, M., Chen, X., Ni, H.M., Lu, B., Stolz, D.B., Clemens, D.L. and Yin, X.M. (2010) Mitigation of acute ethanol-induced hepatotoxicity and steatosis by autophagy. Gastroenterology. 2010 Jul 23. [Epub ahead of print].
Ni, H.M., Bockus, B., Wozniak, A.L., Jones, K., Weinman, S., Yin, X.M., and Ding, W.X*. (2011) Dissecting the Dynamic Turn Over of GFP-LC3 in Autophagolysosomes. Autophagy. 7(2):54-70. * correspondence author. PMID: 21107021.
Ding, W.X., Li, M., and Yin, X.M. (2011) Selective taste of ethanol-induced autophagy for mitochondria and lipid droplets. Autophagy. 7(2):248-249. PMID: 21150309. Cover Story*
Ding, W.X*., Manley, S., and Ni, H.M. (2011) The emerging role of autophagy in alcoholic liver disease. Exp. Biol. Med. 1;236(5):546-56. PMID: 21478210. * correspondence author.
Li., H., Wang, P., Sun, Q., Ding, W.X., Yin, X.M., Sobol., R.W., Stolz, D.B., Yu, J., and Zhang, L. (2011). Following cytochrome c release, autophagy is inhibited during chemotherapy-induced apoptosis by caspase-8-mediated cleavage of Beclin-1. Cancer Res. 71(10): 3625-34. PMID: 21444671.
Mei., S., Ni, H.M., Manley, S., Bockus, A., Kassel, K., Luyendyke, J., Copple, B., and Ding, W.X*. (2011) Differential role of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J Pharmacol Exp Ther. 339(2):487-98. PMID: 21856859 * correspondence author. Highlighted article in JPET.
Ni, H.M., Bockus, A., Jaeschke, H. and Ding, W.X*. (2012) Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology . 55(1):222-32. PMID:21932416. * correspondence author. Faculty of 1000 Biology: (http://f1000.com/13759957).
Ni, H.M., Jaeschke, H. and Ding, W.X*. Targeting autophagy for drug-induced liver injury. (2012) Autophagy. 1;8(4). PMID: 22441014. * correspondence author.
Ni, H.M., Boggess, N, Magill, M., Lebofsky,M., Borude,P., Apte,U., Jaeschke, H and Ding. W.X.* (2012) Liver specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury. Toxi. Sci. (Cover Story). *. 127 (2): 438-450. correspondence author. PMID: 22491424.
Jaeschke, H and Ding, W.X. (2012) Autophagy and acetaminophen hepatotoxicity: how useful are Atg7-deficient mice? Journal of Gastroenterology. 47(7):845-6. PMID: 22565638.
Ding, W.X*. and Yin, X.M. (2012) Mitophagy: Mechanisms, Pathophysiological Role and Analysis. Biological Chemistry. 393(7):547-64. PMID: 22944659. Invited review . * correspondence author.
Ni, H.M, Williams, J., Yang, H, Shi, Y.H., Fan, J and W.X. Ding *. (2012). Targeting autophagy for liver diseases. Pharm. Res. Invited review. Jul 31 Epub ahead of print. PMID: 22871337.* correspondence author.
Klionsky, D., ..., Ding, W.X., ..et al. Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy in Higher Eukaryotes. (2012) Autophagy. 8(4):445-544. PMID: 22966490.
Ding WX*, Li M, Biazik JM, Morgan DG, Guo F, Ni HM, Goheen M, Eskelinen EL, Yin XM. (2012) Electron Microscopic analysis of a spherical mitochondrial structure. J. Biol. Chem. 287(50):42373-8. * correspondence author. PMID: 23093403.
Ding, W.X.*, Guo, F.L., Ni, H.M., Bockus, A., Manley, S., Xie, T., Stolz, D.B., Eskelinen, E.L., Jaeschke, H. and Yin, X.M. (2012) Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. J Biol. Chem. 287(50):42379-88.. * correspondence author. PMID: 23095748.
Chen D, Chen X., Li, M., Zhang, H., Ding, W.X. and Yin, X.M. (2013) CCCP-Induced LC3 lipidation depends on Atg9 whereas FIP200/Atg13 and Beclin 1/Atg14 are dispensable. Biochem Biophys Res Commun. 432(2):226-30. PMID: 22842577.
Czaja M, Ding, W.X., Donohue,T.M., Friedman, S.L., Kim, J.S., Komatsu, M., Lemasters,J.J., Lemoine, A., Lin, J.D., Ou, J.H., Perlmutter,D.H., Randall, G., Ray, R.B., Tsung, A., and Yin, X.M. (2013) Functions of autophagy in normal and diseased liver. Autophagy. 9(8):1131-58. PMID: 23774882.
Ramachandran, A., McGill , M.R., Xie, Y., Ni, H.M., Ding, W.X. and Jaeschke, H. (2013) The Receptor Interacting Protein Kinase 3 is a Critical Mediator of Acetaminophen-induced Hepatocyte Necrosis in Mice. Hepatology. Epub ahead of print. PMID: 23744808.
Manley, S., Williams, J.A., and Ding, W.X. (2013) The pathophysiological role of p62 in the liver. Experimental Biology and Medicine. Experimental Biology and Medicine. 238(5):525-38. PMID: 23856904.
Ni, H.M., Duo, K., Zhao, J., Goldberg, A.L., and Ding, W.X. (2013). Critical Roles of FoxO3 in Alcohol-Induced Autophagy and Hepatotoxicity. American J of Pathology. 84(10):103511. PMID: 24095927. Selected as AJP Press Release.
Williams JA, Hou, Y., Ni, H.M, and Ding, W.X. (2013) Role of intracellular calcium in proteasome inhibitor MG132-induced ER stress, autophagy and cell death. Pharm Res. 30(9):2279-89. PMID: 23893020.
Bi L, Chiang JY, Ding WX, Dunn W, Roberts B, Li T. (2013) Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice. J. Lipid Res. 54(10):2754-62. PMID: 23904453.
Yin, X.M and Ding, W.X. (2013) The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation. Autophagy. 9(11):1687-1692. PMID: 24162069.
Ni, H.M, Williams, J.A., Jaeschke. H and Ding, W.X. (2013) Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver. Redox Biology. 1(1): 427-432. PMID: 24191236.
Ding, W.X. (2013) Induction of autophagy, a promising approach for treating liver injury. Hepatology. 59(1):340-3. PMID: 23775596.
Ding, W.X. (2014) Drinking Coffee Burns Hepatic Fat by Inducing Lipophagy Coupled with Mitochondrial ß-Oxidation. Hepatology. 59(4):1235-8. PMID:24114874.
Manley, S., Woolright, B., Apte, U., Jaeschke, H., Guo, G and Ding, W.X. (2014) Suppression of Autophagic Process by Bile Acids in Hepatocytes. Toxi Sci .137(2):478-90. PMID: 24189133.
Ni, H.M., Woolbright, B., Copple, B, Luyendyke, J., Cui, W., Jaeschke, H and Ding, W.X. (2014) Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J of Hepatology 2014 May Epub Ahead of Print. PMID: 24815875.
Williams, J, Manley, S and Ding, W.X. (2014) New advances and therapeutic targets for alcoholic liver diseases. World J of Gastroenterology 20(36):12908-12933. PMID: 25278688. PMCID: PMC4177473.
Li Y., Wang S., Ni, H.M., Huang H. and Ding, W.X. (2014) Autophagy in alcohol-induced multi-organ injury: mechanisms and potential therapeutic targets. BioMed Research International. 2014:498491. PMID: 25140315. PMCID: PMC4124834
Williams, J, Ni, H.M., Hayness, A, Manley, S., Li, Y., Jaeschke, H. and Ding, W.X. (2015) Chronic deletion and acute knockdown of Parkin have differential responses in acetaminophen-induced mitophagy and liver injury in mice. J. Biol. Chem. 290(17):10934-46. PMID: 25752611. PMCID: PMC4409255
Yang, H., Peng, Y.F., Ni, H.M., Li, Y., Shi, Y.H, Ding, W.X*. and Fan,J. (2015) Basal autophagy and feed back activation of Akt are associated with resistance to metformin-induced inhibition of hepatic tumor cell growth. PloS One. 2015 Jun 25;10(6):e0130953. eCollection 2015. PMID 26111001.
Williams, J, Ni, H.M., and Ding, W.X. (2015) Parkin Regulates Mitophagy and Mitochondrial Function to Protect Against Alcohol2 induced Liver Injury and Steatosis in Mice. American J Physiol-Gastrointestinal and Liver Physiology. 2015 Jul 9:ajpgi.00108.2015. doi: 10.1152/ajpgi.00108.2015. PMID: 26159696.