Wen-Xing Ding, PhD

Associate Professor
PhD, National University of Singapore, Singapore, 2002
Postdoctoral Fellowship, University of Pittsburgh, 2005


Research Focus

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.

Ding Image 1
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 Image 2

 

 

 

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.

Ding Image 3
CCCP induces Parkin-mediated mitophagy. Hela cells were transfected with mCherry parkin and treated with CCCP for 6 hrs.
Ding et al., JBC 2010


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.

Ding Image 4

Ni et al., Hepatology 2012; Ni et al., Autophagy, 2012; Ni et al., Toxi Sciences 2012; Ni et al., Pharm. Res. 2012

 

Selected Publications (recent 5 years)

Chen X, Ding, W.X. Ni, H.M., Gao, W., Shi, Y.H., Gambotto, A.A., Fan, J., Beg, A.A. and Yin, X.M. (2007) Bid-independent Mitochondria Activation in TNF{alpha}-induced Apoptosis and Liver Injury. Mol Cell Biol. 27(2):541-53.

Ding, W.X. Ni, H.M., Gao, W., Hou, Y.F., Melan, M.A., Chen X, Stolz, D.B., Shao, Z.M., and Yin, X.M. (2007) Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem. 282(7):4702-10.  *Faculty of 1000 Biology (http://f1000biology.com/article/id/1070875).

 Ding, W.X., Ni, H.M, Chen, X., Yu, J., Zhang, L., and Yin, X.M. (2007)  A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells. Mol Cancer Ther. 6(3):1062-9. * Cover story.

 Ding, W.X. Ni, H.M., Gao, W., Yoshimori, T., Stolz, D.B., Ron, D., and Yin, X.M. (2007) Linking of Autophagy to Ubiquitin-Proteasome System Is Important for the Regulation of Endoplasmic Reticulum Stress and Cell Viability. Am J Pathol. 171(2):513-24. * Top 50 most read AJP paper.

Ding, W.X*. Ni, H.M.,and Yin, X.M. (2007) Absence of bax switched MG132-induced apoptosis to non-apoptotic cell death that is suppressed by transcriptional and translational inhibitors. Apoptosis. 12(12):2233-44. * correspondence author.

Ding, W.X., and Yin, X.M. (2008) Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy. 4(2):141-50.  

Yin, X.M., Ding, W.X., and Gao, W. (2008) Autophagy in the liver. Hepatology. 47(5):1773-85. Review.

Gao, W., Ding, W.X., Stolz, D., and Yin, X.M. (2008) Induction of macroautophagy by exogenously introduced calcium. Autophagy. 30;4(6). PMCID: PMC2696695.

Shi, Y.H., Ding, W.X., Zhou, J., He, J.Y., Xu, Y., Gambotto, A.A., Rabinowich, H., Fan, J. and Yin, X.M. (2008)  Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence. Hepatology. 48(2):497-507.

Ni, H.M., Chen, X, Ding, W.X., Schuchmann, M., and Yin, X.M. (2008) Differential Roles of JNK in ConA/GalN and ConA-Induced Liver Injury in Mice.  Am J Pathol. 173(4):962-72

Ding, W.X., and Yin, X.M. (2009) Analyzing macroautophagy in hepatocytes and the liver. Methods Enzymol.  453: 397-416.

Ding, W.X. Ni, H.M., Gao, W., Chen, X., Kang, J.H., Stolz, D.B., Liu, J., and Yin, X.M. (2009) Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol Cancer Ther. 8(7):2036-45.

Gao, W., Kang, J.H., Liao, Y., Ding, W.X., Gambotto, A., Watkins, S., Liu,Y.J., Stolz, D.B. and Yin, X.M. (2010) Biochemical isolation and characterization of the tubulovesicular LC3-positive autophagosomal compartment. J Biol Chem 2010 Jan 8;285(2):1371-83. PMID: 19910472.

Ding, W.X. (2010). The role of autophagy in liver physiology and pathophysiology. World J Biol Chem. 1 (1): 3-12. PMID: 21540988

Ni, H.M., Ni HM, Baty CJ, Li N, Ding WX, Gao W, Li M, Chen X, Ma J, Michalopoulos GK, and Yin XM X.M. (2010)  Bid Regulates Murine Hepatocyte Proliferation by Controlling ER Calcium Homeostasis. Hepatology 52(1):338-48. PMID: 20578150.

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 Sotry*

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 formationMitochondrial Phagosome Formation Represents. J Biol. Chem. 287(50):42379-88.. * correspondence author.  PMID: 23095748.

Last modified: Jul 16, 2013

Ding

Contact

Wen-Xing Ding, PhD
Associate Professor

4067 HLSIC; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160

P: (913) 588-9813
F: (913) 588-7501
wxding@kumc.edu

Curriculum Vitae

ID=x9912