Suppression of mitochondrial complex I influences cell metastatic properties
Authors: Aifen Zhou
Hao Lu
Xuelian He
Yong Chen
Xin Yue
Yanxiang Wu
Guochang Huang
Peiwei Zhao
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: Mitochondrial dysfunction; Tumorigenesis; Metastasis; Mitochondrial Complex I; GRIM-19
Affiliations: Central Laboratory, Wuhan Medical and Healthcare Center for Women and Children, Hubei, China. 

Abstract:  Despite the fact that mitochondrial dysfunction has an important role in tumorigenesis and metastasis, the underlying mechanism remains to be elucidated. Mitochondrial Complex I (NADH:ubiquinone oxidoreductase) is the first and the largest protein complex of the mitochondrial electron-transport chain (ETC),which has an essential role in maintaining mitochondrial function and integrity. In this study, we separately knocked down two subunits of mitochondrial complex I, GRIM-19 or NDUFS3, and investigated their effects on metastatic behaviors and explored the possible mechanisms. Our data showed that stable down-modulation of GRIM-19 or NDUFS3 decreased complex I activity and reactive oxygen species (ROS) production; led to enhanced cell adhesion, migration, invasion, and spheroid formation; and influenced the expressions of extracellular matrix (ECM) molecules and its related proteins. We also observed that the expressions of GRIM-19, NDUFS3, and ECM elements were correlated with invasive capabilities of breast cancer cell lines. These results suggest that inhibition of complex I affects metastatic properties of cancer cells, and mitochondrial ROS might play a crucial role in these processes by regulating ECM. 

Retracted: No

PubPeer comments:
 This paper has an April 2014 correction that reads: *There is an error in one result of this article. Knockdown of GRIM-19 did not inhibit cell proliferation as reported, but increased it. Please note the following changes to the text: The third paragraph of the Results section should read:  In addition to the cell-matrix interaction, we also examined cell-cell adhesion by spheroid formation assay in three-dimensional culture. We observed that round and tight spheroids were formed at 48 hr in G19 and p30 cells, while no obvious spheroid was observed in WT and SC at the same time point (Figure 2F). In order to exclude the possibility that the increased migration and invasion in knockdown cells were due to increased cell proliferation, we used mitomycin C to treat the cell lines for 2 hours to arrest cell proliferation before wound healing and transwell migration assays (Please see the method part of cell migration, invasion assay in page 6). In addition, we examined the cell proliferation rate and found that the proliferation rates in the G19 or p30 cells were significantly increased (p 0.01) (Figure 2G). These observations demonstrated that the suppression of GRIM-19 or NDUFS3 in HeLa cells promoted cell adhesion, migration, invasion and spheroid formation, and increased the cell proliferation. * *The second sentence in the third paragraph of the Discussion section should read:  Our results showed that knockdown of GRIM-19 or NDUFS3 induced EMT, enhanced cell adhesion, migration, invasion, spheroid formation, and increased cell proliferation. This change does not alter the main conclusions of this article.* , 
 Not addressed in the Correction is an unexpected similarity between the WT and SC panels in Figure 2A. Shown here with red boxes. This concern was reported to the journal in 2015, with a friendly reminder in 2016, but no response so far. ![file] ,