Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.



Science Signaling:
A Systems Approach for Decoding Mitochondrial Retrograde Signaling Pathways
Sehyun Chae, Byung Yong Ahn, Kyunghee Byun, Young Min Cho, Myeong-Hee Yu, Bonghee Lee, Daehee Hwang, and Kyong Soo Park (26 February 2013)
Sci. Signal. 6 (264), rs4-rs4. [DOI: 10.1126/scisignal.2003266]
Abstract »   Full Text »  PDF » 
Posted E-Letters:

Mitochondrial Retrograde Signaling Pathways

We would like to congratulate Kyong Soo Park and colleagues for their study on decoding mitochondrial retrograde signaling pathways. The authors used cells with an A3243G mutation (mt3243) in the leucine transfer RNA (tRNALeu) to explore mitochondrial retrograde signaling pathways. We would like to ask Kyong Soo Park and colleagues whether mutations in any other mtDNA locus would activate the same retrograde signaling pathways? If ROS is the activator of retrograde signaling, would ROS from outside the cell cause the same effect?

Contributed by

Shida Chen and Xiulan Zhang
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University

An Alternative Approach for Decoding Mitochondrial Retrograde Signaling

In the interesting and comprehensive study by Chae et al., the authors engineered cells to have quantitative variation in the amount of mitochondrial DNA by using a mutation (mt3243) that reduced the expression of proteins controlling oxidative phosphorylation and mitochondrial function and induced mitochondrial retrograde signaling pathways. In our study, which was published two years ago, we used a similar, but distinct, approach for investigation of mitochondrial retrograde signaling pathways based on a creation of mitochondrial DNA-depleted (ρ0) cells (1). ρ0 human skin fibroblasts (HSFs) with suppressed oxidative phosphorylation were characterized by significant changes in the expression of 2100 nuclear genes encoding numerous protein classes (including transcription factors such as C/EBP, NF-ATc1, and HIF1-alpha), by changes in signaling through the NF-κB and STAT3 pathways, and by decreased activity of the mitochondrial death pathway compared to the parental ρ+ HSFs. In contrast, the extrinsic TRAIL-TRAIL Receptor-mediated death pathway remained highly active in ρ0 cells. Global gene expression analysis using microarray and qRT-PCR demonstrated, furthermore, that mRNA expression levels of many growth factors and their adaptor proteins (FGF13, HGF, IGFBP4, IGFBP6, IGFL2), cytokines (IL-6, IL-17B,IL-18,IL-19 and IL-28B), and cytokine receptors (IL-1R1, IL-21R, IL-31RA) were substantially decreased in ρ0 HSFs. Some of these genes were transcriptional targets of NF-κB and STAT3, and their protein products could regulate the STAT3 signaling pathway. On the other hand, upregulated expression of other sets of nuclear genes, including Toll-like receptors 3 and 4, was revealed in ρ0 HSF. Ionizing radiation further induced expression of several NF-κB-STAT3 target genes, including IL-1A, IL-1B, IL-6, PTGS2/COX2, and MMP12, in ρ+ HSFs, but this response was substantially decreased in ρ0 HSFs. Our results indicated that NF-κB activation was partially lost in ρ0 HSFs, resulting in downregulation of the basal or radiation-induced expression of numerous NF-κB targets, further suppressing IL-6-JAK2-STAT3 signaling that, in concert with NF-κB-regulated protection against TRAIL-induced apoptosis. Despite the different approaches used in the study of Chae et al. and in our study, a significant similarity was revealed in both studies in the regulation of the nuclear gene expression by mitochondrial retrograde signaling pathways.


1. V. N. Ivanov, S. A. Ghandhi, H. Zhou, S. X. Huang, Y. Chai, S. A. Amundson, T. K. Hei, Radiation response and regulation of apoptosis induced by a combination of TRAIL and CHX in cells lacking mitochondrial DNA: A role for NF-κB-STAT3-directed gene expression. Exp. Cell Res. 317, 1548-1566 (2011). [PubMed]

Contributed by

Vladimir N. Ivanov
Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882