Center for Metabolic and Degenerative Diseases, the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX, USA.
Microscopy Core, the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX, USA.
FASEB J. 2020 Jun;34(6):8265-8282. doi: 10.1096/fj.201903100RR. Epub 2020 Apr 15.
Dynamin-Related-Protein 1 (DRP1) critically regulates mitochondrial and peroxisomal fission in multicellular organisms. However, the impact of DRP1 on other organelles, especially its direct influence on ER functions remains largely unclear. Here, we report that DRP1 translocates to endoplasmic reticulum (ER) in response to β-adrenergic stimulation. To further investigate the function of DRP1 on ER-lipid droplet (LD) dynamics and the metabolic subsequences, we generated an adipose tissue-specific DRP1 knockout model (Adipo-Drp1 ). We found that the LDs in adipose tissues of Adipo-Drp1 mice exhibited more unilocular morphology with larger sizes, and formed less multilocular structures upon cold exposure. Mechanistically, we discovered that abnormal LD morphology occurs because newly generated micro-LDs fail to dissociate from the ER due to DRP1 ablation. Conversely, the ER retention of LDs can be rescued by the overexpressed DRP1 in the adipocytes. The alteration of LD dynamics, combined with abnormal mitochondrial and autophagy functions in adipose tissue, ultimately lead to abnormalities in lipid metabolism in Adipo-Drp1 mice.
动力相关蛋白 1（DRP1）在多细胞生物中对线粒体和过氧化物酶体的分裂起关键作用。然而，DRP1 对其他细胞器的影响，特别是其对内质网（ER）功能的直接影响，在很大程度上仍不清楚。在这里，我们报告 DRP1 在受到β-肾上腺素刺激时会转移到内质网（ER）。为了进一步研究 DRP1 对 ER-脂滴（LD）动力学和代谢后续过程的功能，我们生成了一种脂肪组织特异性 DRP1 敲除模型（Adipo-Drp1）。我们发现，Adipo-Drp1 小鼠脂肪组织中的 LD 表现出更单室形态，且大小更大，在寒冷暴露下形成更少的多室结构。从机制上讲，我们发现由于 DRP1 缺失，新生成的微 LD 无法与 ER 分离，导致 LD 形态异常。相反，在脂肪细胞中过表达 DRP1 可以挽救 LD 在内质网上的滞留。LD 动力学的改变，加上脂肪组织中线粒体和自噬功能的异常，最终导致 Adipo-Drp1 小鼠的脂质代谢异常。
