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突变会导致自噬、线粒体清除和人类运动障碍的缺陷。在这里，我们发现 Vps13D 在 Vmp1 下游和 Marf/Mfn2 上游的通路中发挥作用。与vps13d一样， vmp1突变细胞在自噬、线粒体大小和清除方面表现出缺陷。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。值得注意的是，Vps13D 在线粒体和 ER 接触中的功能在果蝇和人类细胞之间是保守的，包括来自患有VPS13D突变相关神经系统症状的患者的成纤维细胞。 vps13d突变体的 Marf/MFN2（线粒体融合调节因子）水平增加。重要的是， marf/MFN2的缺失会抑制vps13d突变表型，包括线粒体和 ER 接触。这些发现表明，Vps13d 在线粒体和内质网接触、线粒体融合和自噬之间的调节点发挥作用，并有助于解释 Vps13D 如何导致疾病。