Control of beta cell identity by the mitochondrial life cycle

通过线粒体生命周期控制 β 细胞身份

• 批准号: 10454761
• 负责人: Scott Soleimanpour
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454761
• 关键词: Address; Anabolism; Antioxidants; B-Cell Development; Back; Beta Cell; Biogenesis; Biosensor; Blood Glucose; Cell Survival; Cells; Characteristics; Chromatin; Chronic Disease; DNA; Data; Defect; Diabetes Mellitus; Diabetes prevention; Ensure; Environment; Equilibrium; Etiology; Exhibits; Failure; Feedback; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Glucose; Goals; Health; Human; Hyperglycemia; Impairment; Insulin; Lead; Life Cycle Stages; Maintenance; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Pancreas; Patients; Peripheral; Pharmacology; Physiological; Power Plants; Quality Control; Reporting; Respiration; Role; Signal Pathway; Signal Transduction; Structure; Structure of beta Cell of islet; Techniques; Testing; Veterans; biological adaptation to stress; diabetes pathogenesis; fatty acid metabolism; genetic approach; in vivo; insight; insulin secretion; islet; metabolomics; mitochondrial dysfunction; novel; oxidative damage; preservation; programs; response; stem cells; tool; transcriptomics

Diabetes results from insufficient functional pancreatic β-cell mass to meet peripheral insulin demands. β-cell failure can occur in T2D due to loss of β-cell identity or de-differentiation, with recent studies suggesting that loss of the mitochondrial gene expression program heralds the immature β-cell state. β-cells rely upon mitochondrial respiration to generate the energy necessary for the metabolic demands of insulin biosynthesis, processing, and secretion. Indeed, defects in mitochondrial structure, function, and DNA levels have been reported in the β-cells of patients with type 2 diabetes (T2D). Defects in mitochondrial structure and function are characteristic of impairments in the mitochondrial life cycle, which maintains functional mitochondrial mass via a balance of biogenesis and turnover. It is not clear, however, if impaired mitochondria are necessary and sufficient to directly induce β-cell immaturity. Interestingly, our preliminary data suggest that genetic loss of biogenesis or mitophagy reduces β-cell maturity and mass, which is not due to impaired β-cell replication or survival. Therefore, our goal is to dissect the mechanistic contribution of mitochondrial biogenesis and turnover to β-cell maturity and elucidate their contribution to diabetes pathogenesis. The central hypothesis to be tested is that defects in the mitochondrial life cycle induce a retrograde signaling cascade that impairs β-cell identity. We will test this hypothesis by the following approach: Specific Aim 1 will elucidate the effect of metabolic overload on the mitochondrial life cycle and its control of β-cell identity. Specific Aim 2 will determine the contribution of mitochondria derived oxidative damage to the development of β-cell immaturity. Specific Aim 3 will delineate the role of the integrated stress response to consolidate retrograde signals inducing β-cell immaturity following mitochondrial dysfunction. We anticipate obtaining a clear understanding of the importance and translational relevance of the mitochondrial life cycle by revealing the key effectors that mediate mito-nuclear crosstalk and impact β-cell identity. These results should re-define the role of mitochondria in diabetes pathogenesis and could open new possibilities to re-program immature β-cells back to a mature state to treat diabetes in Veterans.

糖尿病是由功能性胰腺β细胞质量不足而导致的，无法满足外周胰岛素需求。 β细胞 由于β细胞身份的丧失或去差异的丧失，可能在T2D中发生故障，最近的研究表明损失 线粒体基因表达程序预示着未成熟的β细胞状态。 β细胞依靠线粒体 呼吸以产生胰岛素生物合成，加工和代谢需求所必需的能量 分泌。实际上，在β细胞中报道了线粒体结构，功能和DNA水平的缺陷 2型糖尿病患者（T2D）。线粒体结构和功能的缺陷是 线粒体生命周期中的损害，该生命周期通过平衡保持功能性线粒体质量 生物发生和周转。但是，尚不清楚线粒体是否需要且足以直接 诱导β细胞不成熟。有趣的是，我们的初步数据表明生物发生或线粒体的遗传丧失 降低β细胞的成熟度和质量，这不是由于β细胞复制或存活受损所致。因此，我们的目标 是为了剖析线粒体生物发生的机理贡献，并营业额对β细胞成熟度并阐明 它们对糖尿病发病机理的贡献。要测试的中心假设是 线粒体生命周期会诱导逆行信号级联，损害β细胞身份。我们将测试这个 通过以下方法假设：特定目标1将阐明代谢过载对 线粒体生命周期及其对β细胞身份的控制。具体目标2将决定 线粒体对β细胞不成熟的发展产生了氧化损伤。具体目标3将描绘 综合应力反应对固结逆行信号诱导的β细胞不成熟的作用 线粒体功能障碍。我们预计对重要性和翻译的清晰了解 线粒体生命周期的相关性是通过揭示介导线粒体核串扰和 影响β细胞的身份。这些结果应重新定义线粒体在糖尿病发病机理中的作用，并且可以 打开新的可能性，以重新编程不成熟的β细胞回到成熟状态，以治疗退伍军人中的糖尿病。