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

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $418,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10902012
- **Project number:** 5R01AG082740-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Eric H Baehrecke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902012

## Citation

> US National Institutes of Health, RePORTER application 10902012, VPS13D, organelle contact, and cellular stress in models of disease (5R01AG082740-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10902012. Licensed CC0.

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