Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development
James L Shen1, Tina M Fortier1, Yan G Zhao1
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Abstract:
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.
Insights
Vps13D protein is crucial for cellular processes like autophagy and mitochondrial health. Its dysfunction links to neurological disorders by affecting mitochondria-ER contact and fusion.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Mutations in Vps13D are linked to impaired autophagy, mitochondrial clearance, and human movement disorders.
- Vps13D's precise cellular function and its role in disease pathogenesis remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular pathway and cellular functions of Vps13D.
- To investigate the role of Vps13D in regulating mitochondria-endoplasmic reticulum (ER) contact and its implications in disease.
Main Methods:
- Utilized genetic analysis in model organisms and human cell lines.
- Investigated the relationship between Vps13D, Vmp1, and Marf/Mfn2.
- Assessed cellular phenotypes including autophagy, mitochondrial morphology, and mitochondria-ER contact.
Main Results:
- Vps13D functions downstream of Vmp1 and upstream of Marf/Mfn2, impacting autophagy and mitochondrial clearance.
- Vps13D plays a novel role in regulating mitochondria-ER contact, a function conserved across species.
- Loss of Marf/Mfn2 suppresses Vps13D mutant phenotypes, highlighting its role in mitochondrial fusion.
Conclusions:
- Vps13D acts as a key regulator at the intersection of mitochondria-ER contact, mitochondrial fusion, and autophagy.
- Understanding Vps13D's function provides insights into the molecular basis of VPS13D mutation-associated neurological disorders.
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