title: A systems approach for decoding mitochondrial retrograde signaling pathways.
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 γ, 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.
authors: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors: Sehyun
authors: S
authors: Chae
authors: Byung Yong
authors: BY
authors: Ahn
authors: Kyunghee
authors: K
authors: Byun
authors: Young Min
authors: YM
authors: Cho
authors: Myeong-Hee
authors: MH
authors: Yu
authors: Bonghee
authors: B
authors: Lee
authors: Daehee
authors: D
authors: Hwang
authors: Kyong Soo
authors: KS
authors: Park
mesh_terms: D015153:Blotting, Western; D002467:Cell Nucleus / Q000502:physiology*; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017354:Point Mutation / Q000235:genetics; D012356:RNA, Transfer, Leu / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D049490:Systems Biology / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012356:RNA, Transfer, Leu; D017382:Reactive Oxygen Species; D047490:Retinoid X Receptor alpha; D014157:Transcription Factors; D048670:MAP Kinase Kinase 4