Control of beta cell identity by the mitochondrial life cycle

糖尿病是由于功能性胰腺β细胞质量不足以满足外周胰岛素需求而引起的。β细胞 由于β细胞身份的丧失或去分化，T2D中可能发生失败，最近的研究表明， 的线粒体基因表达程序预示着不成熟的β细胞状态。β细胞依赖于线粒体 呼吸，以产生胰岛素生物合成、加工和代谢所需的能量， 分泌物事实上，在β细胞中已经报道了线粒体结构、功能和DNA水平的缺陷。 2型糖尿病（T2 D）患者的。线粒体结构和功能的缺陷是 线粒体生命周期中的损伤，其通过平衡 生物发生和周转。然而，目前尚不清楚受损的线粒体是否是直接影响 诱导β细胞不成熟。有趣的是，我们的初步数据表明， 降低β细胞成熟度和质量，这不是由于β细胞复制或存活受损。因此，我们的目标 是剖析线粒体生物发生和周转对β细胞成熟的机制贡献， 它们对糖尿病发病机制的贡献。要检验的中心假设是， 线粒体生命周期诱导损害β细胞身份的逆行信号级联。我们将测试这个 具体目标1将阐明代谢超负荷对代谢的影响。 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 线粒体源性氧化损伤导致β细胞发育不成熟。具体目标3将描述 整合应激反应在巩固诱导β细胞不成熟的逆行信号中的作用 线粒体功能障碍我们期望获得一个清晰的理解的重要性和翻译 通过揭示介导线粒体核串扰的关键效应子， 影响β细胞特性。这些结果应该重新定义线粒体在糖尿病发病机制中的作用， 为将未成熟的β细胞重新编程为成熟状态以治疗退伍军人糖尿病开辟了新的可能性。

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.