Mitophagy Dependent Regulation of Mammary Gland Differentiation

总结 线粒体作为许多代谢过程的中心枢纽，通过感测和响应细胞内的代谢过程， 环境以维持体内平衡。因此，它们的破坏是发病和进展的关键因素， 包括代谢紊乱、神经退行性疾病和癌症。 线粒体内稳态主要通过靶向的细胞因子对受损线粒体的再循环来维持。 自噬，称为线粒体自噬。线粒体自噬是组织特异性的，并且响应于细胞应激和细胞凋亡而发生。 分化线索分化提示的线粒体自噬通常被称为程序性线粒体自噬， 因其对表观遗传状态、细胞命运决定、代谢适应和 分化虽然这些和其他影响已被归因于线粒体自噬，很少有人知道， 上游信号通路诱导线粒体自噬以满足特定的细胞需要。不同的形态 线粒体的差异存在于出生后的乳腺发育阶段。这表明 线粒体自噬对这个组织的发育起着重要作用。确定 在乳腺发育过程中维持线粒体内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。我们已经证明 Singleminded-2s（SIM2s;由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。我们最近的研究结果利用乳腺- 特异性过表达和低表达的Sim2s转基因小鼠表明，功能性泌乳需要SIM2s， 并且部分地通过与PRKN线粒体自噬复合物的直接相互作用来实现。基于这些新的结果， 我们推测，线粒体自噬依赖的线粒体适应是乳腺功能的关键， 因此，SIM2s是维持线粒体稳态所必需的。为了解决这个假设，我们 提出两个具体目标。在目标1中，我们将确定线粒体自噬驱动的代谢转换所需的 通过将mito-QC小鼠模型与MMTV-Sim2s和Sim2fl/fl杂交的乳腺上皮细胞分化 小鼠评估线粒体自噬和线粒体结构和代谢适应。在目标2中，我们将定义 SIM2、ATM、PINK1/PRKN和LC3之间相互作用的物理基础和功能结果， 线粒体自噬和乳腺分化。成功完成此提案将提供以下见解 迄今未知的机制线粒体适应生理条件下。我们期待结果 这些研究将有助于确定乳腺发育中线粒体适应的机制， 哺乳和癌症

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.