Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Curr Biol. 2021 Jul 26;31(14):3028-3039.e7. doi: 10.1016/j.cub.2021.04.062. Epub 2021 May 20.
Mutations in Vps13D cause defects in autophagy, clearance of mitochondria, and human movement disorders. Here, we discover that Vps13D functions in a pathway downstream of Vmp1 and upstream of Marf/Mfn2. Like vps13d, vmp1 mutant cells exhibit defects in autophagy, mitochondrial size, and clearance. Through the relationship between vmp1 and vps13d, we reveal a novel role for Vps13D in the regulation of mitochondria and endoplasmic reticulum (ER) contact. Significantly, the function of Vps13D in mitochondria and ER contact is conserved between fly and human cells, including fibroblasts derived from patients suffering from VPS13D mutation-associated neurological symptoms. vps13d mutants have increased levels of Marf/MFN2, a regulator of mitochondrial fusion. Importantly, loss of marf/MFN2 suppresses vps13d mutant phenotypes, including mitochondria and ER contact. These findings indicate that Vps13d functions at a regulatory point between mitochondria and ER contact, mitochondrial fusion and autophagy, and help to explain how Vps13D contributes to disease.
Vps13D 突变导致自噬、线粒体清除和人类运动障碍缺陷。在这里，我们发现 Vps13D 在 Vmp1 的下游途径和 Marf/Mfn2 的上游发挥作用。与 vps13d 一样，vmp1 突变细胞表现出自噬、线粒体大小和清除缺陷。通过 vmp1 和 vps13d 之间的关系，我们揭示了 Vps13D 在调节线粒体和内质网 (ER) 接触中的新作用。重要的是，Vps13D 在果蝇和人细胞中线粒体和 ER 接触中的功能是保守的，包括来自患有 VPS13D 突变相关神经症状患者的成纤维细胞。vps13d 突变体中 Marf/MFN2 的水平升高，Marf/MFN2 是线粒体融合的调节剂。重要的是，marf/Mfn2 的缺失抑制了 vps13d 突变体的表型，包括线粒体和 ER 接触。这些发现表明 Vps13d 在调节线粒体和 ER 接触、线粒体融合和自噬的调控点发挥作用，并有助于解释 Vps13D 如何导致疾病。
