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Regulation of Cellular Proliferation by Novel Mitochondrial-Encoded Tumor Suppressors

新型线粒体编码肿瘤抑制剂对细胞增殖的调节

基本信息

批准号：
10389994
负责人：
Changhan Lee
金额：
$ 16.74万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389994
关键词：
ATAC-seq Adenosine Monophosphate Affect Amino Acids Bacteria Basic Science Binding Bioinformatics Cancer Model Cell Cycle Cell Nucleus Cell Proliferation Cell Separation Cell Survival Cell physiology Cells Cellular Stress Chromatin Code Communication Computer Analysis Computing Methodologies Coupled DNA DNA Binding Data Developmental Therapeutics Program Electron Transport Endothelium Eukaryota Eukaryotic Cell Evolution Exhibits FDA approved Foundations Gene Expression Genes Genetic Genetic Diseases Genome Genomic approach Genomics Homeostasis In Vitro Insulin Resistance Language Longevity Machine Learning Malignant - descriptor Malignant Neoplasms Maps Mediating Metabolic Metabolic stress Metabolism Mitochondria Mitochondrial DNA Modeling Molecular Molecular Biology Techniques Molecular Genetics Molecular and Cellular Biology Mus Names Normal Cell Normal tissue morphology Nuclear Nuclear Translocation Nutrient Open Reading Frames Organelles Osteoporosis Pathway interactions Patients Peptides Pharmaceutical Preparations Process Property Protein Kinase Proteins Proteomics Publishing RNA Regulation Reporting Resistance Ribosomal RNA Ribosomes Role Signal Transduction Site-Directed Mutagenesis Source Stress System TP53 gene Testing The Cancer Genome Atlas Time Tissue Microarray Tissues Toxic effect Treatment Efficacy Tumor Suppressor Proteins age related antitumor effect base cancer cell cancer genome cancer type cell growth regulation cell type chemotherapy chromatin immunoprecipitation combinatorial comparative diet-induced obesity exhaustion functional genomics genomic data immune function improved in vivo loss of function mitochondrial genome mouse model muscle metabolism mutant new therapeutic target novel prevent response sensor single-cell RNA sequencing therapeutic development tumor

项目摘要

ABSTRACT Cellular compartments are coordinated through a dynamic bidirectional communication network amongst various organelles. Here, we focus on the communication between mitochondria and the nucleus, organelles that each possess their own genomes. The mitochondrial and nuclear genomes have co-evolved for over a billion years and have likely required close communication and cross-regulation. However, whereas mitochondria are known to be regulated by over 1,000 nuclear-encoded proteins, but there is currently no known mitochondrial-encoded factor that actively communicates to and regulates the nucleus. We have recently identified a novel gene encoded within the mitochondrial DNA and named it MOTS-c (Mitochondrial ORF within the Twelve S rRNA type-c). MOTS-c is a small 16 amino acid peptide that regulates metabolic homeostasis, in part, via the master nutrient sensor AMPK (adenosine monophosphate-activated protein kinase). We recently reported that MOTS-c can translocate into the nucleus in response to metabolic stress to bind to chromatin and regulate nuclear gene expression. Further, our preliminary study using a multi-pronged approach, including single cell RNA-seq, bioinformatics (including machine learning), chromatin immunoprecipitation (ChIP) coupled with quantitative PCR (qPCR), and cell sorting, showed that MOTS-c can regulate cellular proliferation; MOTS-c targeted the p53/p21 pathway and ribosomal processes. Considering the important metabolic role of mitochondria in cellular proliferation processes (29), a critical question that remains largely enigmatic is how mitochondrial-encoded factors communicate to the nucleus to coordinate the metabolic shift with gene expression during proliferation. Notably, rapidly dividing cancer cells had undetectable levels of MOTS-c or nuclear-translocation deficiency, suggesting loss of mito-nuclear communication by MOTS-c. Together, cancer may be a genetic disease in which our two genomes exist in a state of disrupted bi-directional communication/regulation, and may serve as a unique model to start understanding the role of MOTS-c in cellular proliferation. Because MOTS-c expression/function was dysregulated and that MOTS-c can negatively regulate cell cycle/proliferation, we hypothesize that MOTS-c is a mitochondrial-encoded tumor suppressor, the first of its kind to be identified, that directly regulates the nucleus to coordinate cellular metabolism with proliferation. We propose three aims to test this hypothesis. First, we will characterize MOTS-c as a tumor suppressor that regulates cell proliferation at the molecular, cellular, genetic level. Second, we will comprehensively map the MOTS-c-dependent functional nuclear genomic landscape using multiple complimentary genomics approach, including single cell RNA-seq, ATAC-seq (chromatin accessibility), and genomic footprinting using ChIP-seq. The data from each genomic approach will be integrated using cutting-edge computational methods, including machine learning, to decipher the message(s) MOTS- c delivers to the nuclear genome to regulate cancer cell proliferation and survival. Lastly, we will determine how MOTS- c-mediated communication to the nucleus can differentially regulate cellular proliferation and stress resistance in normal and malignant cells using mouse models of cancer. If successful, we predict that our study will have broad and lasting impact on (i) basic research by introducing the paradigm-shifting concept of mitochondrial-encoded tumor suppressors that coordinate cellular metabolism and proliferation and (ii) therapeutic development by revealing mtDNA as a source of novel drug targets (currently there are no FDA-approved drugs based on the mitochondrial genome).

摘要