Chae, Sehyun Ahn, Byung Yong Byun, Kyunghee Cho, Young Min Yu, Myeong-Hee Lee, Bonghee Hwang, Daehee Park, Kyong Soo 2024-01-20T13:01:28Z 2024-01-20T13:01:28Z 2021-09-01 2013-02 1937-9145 https://pubs.kist.re.kr/handle/201004/128344 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 alpha), reactive oxygen species, kinase JNK (c-JUN N-terminal kinase), and transcriptional coactivator PGC1 alpha (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha). 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. English AMER ASSOC ADVANCEMENT SCIENCE A Systems Approach for Decoding Mitochondrial Retrograde Signaling Pathways Article 10.1126/scisignal.2003266 1 SCIENCE SIGNALING, v.6, no.264 SCIENCE SIGNALING 6 264 N scie scopus 000315449600002 2-s2.0-84875199413 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article 9-CIS RETINOIC ACID TRANSCRIPTION FACTOR SKELETAL-MUSCLE HYDROGEN-PEROXIDE OXIDATIVE STRESS GENE-EXPRESSION X-RECEPTOR PROTEIN-SYNTHESIS REDOX REGULATION VITAMIN-A