VPS13D, organelle contact, and cellular stress in models of disease

摘要 细胞器的接触和交流对细胞的健康很重要。更改本条例 内质网和线粒体等细胞器之间的关系， 影响离子、脂类和蛋白质的转移，影响细胞器间的动力学和 与疾病相关的。我们的假设是线粒体和内质网接触的缺陷导致 由于自噬(有丝分裂)导致线粒体清除减少，细胞应激增加，以及 炎症是与年龄相关的进行性运动障碍的基础。为了支持…… 我们的假设是，我们发现了以前未描述的脂转移蛋白VPS13D为 线粒体大小和有丝分裂的调节者，并表明VPS13D影响ER和 线粒体接触。重要的是，这些表型在不同的类群之间是保守的， 包括果蝇和人类。此外，我们最近还发现VPS13D突变体 细胞具有升高的应激和炎症标志物。VPS13D丢失导致 进行性和年龄相关的人类疾病，包括痉挛共济失调和截瘫。 值得注意的是，我们最近开发的VPS13D条件性基因敲除突变小鼠模型 在患者和患者来源的细胞中表现出与观察一致的表型。 我们的目标是研究VPS13D突变相关线粒体和内质网的作用 患者来源的成纤维细胞中的接触和我们最近开发的基因敲除 老鼠模型。在这里，我们建议：(1)确定VPS13D中细胞器的接触是否改变 患者来源的成纤维细胞影响年龄相关的细胞缺陷在有丝分裂，应激和 炎症，(2)检查VPS13D条件基因敲除突变小鼠的细胞器缺陷 接触和神经表型；(3)研究VPS13D通路基因 抑制疾病表型。细胞器接触改变，自噬， 压力、炎症和与年龄相关的疾病说明了 研究细胞中的这些过程与动物健康之间的关系。

ABSTRACT Organelle contact and communication are important for the health of cells. Alteration of the relationship between organelles, such as endoplasmic reticulum (ER) and mitochondria, influences the transfer of ions, lipids, and proteins, impacts inter-organelle dynamics and is associated with diseases. Our hypothesis is that defects in mitochondria and ER contact result in decreased mitochondrial clearance by autophagy (mitophagy), increased cell stress, and inflammation that underlie age-associated and progressive movement disorders. In support of our hypothesis, we discovered the previously uncharacterized lipid transfer protein VPS13D as a regulator of mitochondrial size and mitophagy, and showed that VPS13D influences ER and mitochondria contact. Importantly, these phenotypes are conserved between diverse taxa, including fruit flies and humans. In addition, we have recently discovered that VPS13D mutant cells possess elevated markers of stress and inflammation. Loss of VPS13D results in progressive and age-associated human disease, including spastic ataxia and paraplegia. Significantly, our recently developed VPS13D conditional knockout mutant mouse model exhibits phenotypes that are consistent with observations in patients and patient-derived cells. Our goal is to characterize the role of VPS13D mutation-associated mitochondria and ER contact in fibroblasts that were derived from patients and our recently developed knockout mouse model. Here we propose to: (1) determine if altered organelle contact in VPS13D patient-derived fibroblasts influences age-associated cell defects in mitophagy, stress and inflammation, (2) examine VPS13D conditional knockout mutant mice for defects in organelle contact and neurological phenotypes, and (3) investigate VPS13D pathway genes for suppression of disease phenotypes. The association of altered organelle contact, autophagy, stress, and inflammation with age-associated disorders illustrates the importance of investigating the relationship between these processes in cell and animal health.