Mitophagy Dependent Regulation of Mammary Gland Differentiation

乳腺分化的线粒体自噬依赖性调节

• 批准号: 10478831
• 负责人: Weston W Porter
• 金额: $ 41.98万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478831
• 关键词: Address; Architecture; Attention; Autophagocytosis; Breast Epithelial Cells; Cell Differentiation process; Cells; Cellular Metabolic Process; Cellular Stress; Citrates; Coenzyme A; Complex; Cues; Data; Development; Disease; Environment; Epigenetic Process; Epithelial; Gene Expression Regulation; Glucose; Histone Acetylation; Homeostasis; Hormones; Human; Lactation; Lactation Disorders; Malignant Neoplasms; Mammary gland; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Morphology; Mouse Mammary Tumor Virus; Mus; Neurodegenerative Disorders; PINK1 gene; Parkin; Pathology; Pathway interactions; Physiological; Play; Process; Protein Family; Publishing; Pyruvate; Recycling; Regulation; Role; Signal Pathway; Signal Transduction; Tissues; Transgenic Mice; base; differential expression; functional outcomes; in vivo; inhibitor; insight; malignant breast neoplasm; mammary gland development; member; mouse model; response; transcription factor; ubiquitin-protein ligase

SUMMARY Mitochondria operate as a central hub for many metabolic processes by sensing and responding to the cellular environment to maintain homeostasis. Consequently, their disruption is a key factor in the onset and progression of many human conditions, including metabolic disorders, neurodegenerative diseases, and cancer. Mitochondrial homeostasis is primarily maintained through the recycling of damaged mitochondria by targeted autophagy, termed mitophagy. Mitophagy is tissue-specific and occurs in response to both cellular stress and differentiation cues. Differentiation-cued mitophagy is often termed programmed mitophagy and has recently gained attention for its contribution to epigenetic status, cell fate decisions, metabolic adaptation and differentiation. Although these and other effects have been attributed to mitophagy, little is known about the upstream signaling pathways that induce mitophagy to meet specific cellular needs. Distinct morphological differences in mitochondria exist during the post-natal stages of mammary gland development. This suggests that mitophagy plays an important to the development of this tissue. Identifying the mechanism by which mitochondrial homeostasis is maintained during mammary gland development will provide much needed insight into the broader role of mitochondrial adaptation in normal development and disease. We have shown that Singleminded-2s (SIM2s; expressed from Sim2), is differentially expressed during mammary gland development and is a key regulator of functional mammary gland differentiation. Our recent results utilizing mammary gland- specific over- and under-expressing Sim2s transgenic mice show that SIM2s is required for functional lactation, and does so, in part, through direct interaction with the PRKN mitophagy complex. Based on these new results, we hypothesize that mitophagy-dependent mitochondrial adaptation is essential for mammary gland functional differentiation and that SIM2s is required to maintain mitochondrial homeostasis. To address this hypothesis we propose two Specific Aims. In Aim 1, we will determine the mitophagy-driven metabolic transition required for mammary epithelial cell differentiation by crossing the mito-QC mouse model with MMTV-Sim2s and Sim2fl/fl mice to assess mitophagy and mitochondrial architecture and metabolic adaptation. In Aim 2, we will define the physical basis for, and functional outcomes of, interactions between SIM2s, ATM, PINK1/PRKN, and LC3 in mitophagy and mammary gland differentiation. Successful completion of this proposal will provide insight into heretofore unknown mechanisms of mitochondrial adaptation under physiological conditions. We expect results from these studies will help define the mechanism of mitochondrial adaptation in mammary gland development, lactation, and cancer.

概括 线粒体通过感测并响应细胞来作为许多代谢过程的中央枢纽 维持体内平衡的环境。因此，它们的破坏是发作和进展的关键因素 在许多人类状况中，包括代谢性疾病，神经退行性疾病和癌症。 线粒体稳态主​​要是通过靶向的线粒体的回收来维持 自噬，称为线粒体。线粒体是组织特异性的，并且是针对细胞应激和 分化线索。分化示意的线粒体通常被称为编程线索，最近有 因其对表观遗传状况的贡献，细胞命运决定，代谢适应和 分化。尽管这些和其他效果归因于线粒体，但对 上游信号通路可诱导线粒体满足特定的细胞需求。独特的形态学 在乳腺发育后产后阶段存在线粒体的差异。这暗示着 线粒体对该组织的发展很重要。确定该机制 在乳腺开发期间维持线粒体稳态将提供急需的见解 线粒体适应在正常发育和疾病中的更广泛作用。我们已经表明 Singlembendend-2s（SIM2S;根据SIM2表达）在乳腺发育过程中差异表达 并且是功能性乳腺分化的关键调节剂。我们最近利用乳腺的结果 特定的过度表达和表达的SIM2S转基因小鼠表明，SIM2S是功能哺乳需要的， 并部分通过与PRKN线粒体复合物直接相互作用来做到这一点。基于这些新结果 我们假设线粒体依赖性线粒体适应对于乳腺功能至关重要 分化和SIM2需要维持线粒体稳态。为了解决这一假设 提出两个具体目标。在AIM 1中，我们将确定线粒体驱动的代谢过渡 通过使用MMTV-SIM2S和SIM2FL/FL的MITO-QC小鼠模型越过乳腺上皮细胞分化 评估线粒体和线粒体结构以及代谢适应的小鼠。在AIM 2中，我们将定义 SIM2S，ATM，PINK1/PRKN和LC3之间相互作用的物理基础和功能结果 线粒体和乳腺分化。成功完成本提案将提供有关 在生理条件下，线粒体适应的迄今未知机制。我们期望结果 通过这些研究将有助于定义乳腺发育中线粒体适应的机制， 哺乳和癌症。