A Systems Approach for Decoding Mitochondrial Retrograde Signaling Pathways

Sehyun Chae^1,2*, Byung Yong Ahn^2*, Kyunghee Byun^3*, Young Min Cho², Myeong-Hee Yu⁴, Bonghee Lee³, Daehee Hwang^1,5,6, and Kyong Soo Park²

¹ School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
² Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
³ Center for Genomics and Proteomics & Stem Cell Core Facility, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon 406-799, Republic of Korea.
⁴ Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
⁵ Department of Chemical Engineering, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
⁶ Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.

Abstract: Mitochondrial dysfunctions activate retrograde signaling from mitochondria to the nucleus. To identify transcription factors and their associated pathways that underlie mitochondrial retrograde signaling, we performed gene expression profiling of the cells engineered to have varying amounts of mitochondrial DNA with an A3243G mutation (mt3243) in the leucine transfer RNA (tRNA^Leu), which reduces the abundance of proteins involved in oxidative phosphorylation that are encoded by the mitochondrial genome. The cells with the mutation exhibited reduced mitochondrial function, including compromised oxidative phosphorylation, which would activate diverse mitochondrial retrograde signaling pathways. By analyzing the gene expression profiles in cells with the mutant tRNA^Leu and the transcription factors that recognize the differentially regulated genes, we identified 72 transcription factors that were potentially involved in mitochondrial retrograde signaling. We experimentally validated that the mt3243 mutation induced a retrograde signaling pathway involving RXRA (retinoid X receptor α), reactive oxygen species, kinase JNK (c-JUN N-terminal kinase), and transcriptional coactivator PGC1α (peroxisome proliferator–activated receptor , coactivator 1 α). This RXR pathway contributed to the decrease in mRNA abundances of oxidative phosphorylation enzymes encoded in the nuclear genome, thereby aggravating the dysfunction in oxidative phosphorylation caused by the reduced abundance of mitochondria-encoded enzymes of oxidative phosphorylation. Thus, matching transcription factors to differentially regulated gene expression profiles was an effective approach to understand mitochondrial retrograde signaling pathways and their roles in mitochondrial dysfunction.

To whom correspondence should be addressed. E-mail: dhhwang{at}postech.ac.kr (D.H.); kspark{at}snu.ac.kr (K.S.P.); bhlee{at}gachon.ac.kr (B.L.)

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