# A Novel Role for Membrane Trafficking in Mitochondrial Homeostasis and Apoptosis

> **NIH NIH F31** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $27,683

## Abstract

Project Summary/Abstract:
 The mitochondrion is a unique organelle that serves as the main site of adenosine triphosphate
(ATP) generation needed for energy in the cell. However, mitochondria also play essential roles in cell death
through apoptosis and necrosis, as well as a variety of crucial functions related to stress regulation, autophagy,
lipid synthesis, and calcium storage. There is a growing appreciation that mitochondrial function is regulated by
the dynamics of its membrane fusion and fission; longer, fused mitochondria are optimal for ATP generation,
whereas fission of mitochondria facilitates mitophagy and cell division, events that have a direct bearing on
cancer tumorigenesis. Despite the significance that mitochondria play in regards to cancer cells, the intricate
regulation of mitochondrial function is only partially understood. Only now, have researchers turned to address
the upstream machinery that regulates mitochondrial function through fusion and fission. The proposed
research strategy will open up new avenues for translational and future clinical studies on the modulation of
mitochondrial function, allowing for novel therapeutics for cancer patients. The first aim of this proposal, to
elucidate the mechanism how EHD1 and Rabankyrin-5 regulate mitochondrial fission, will continue to build
upon recent findings that indicate significant upstream regulation of mitochondrial fission by endocytic
regulatory proteins. This portion of the proposal will characterize the mechanism by which EHD1, an endocytic
regulatory protein, and its interaction partner, Rabankyrin-5, regulate VPS35, an endocytic protein that
modulates mitochondrial fission. The mechanism by which EHD1 and Rabankyrin-5 regulate VPS35 will be
elucidated by studying the physical and functional relationships between EHD1 and VPS35 by various
techniques, including CRISPR/Cas9 gene-edited cells, targeted amino acid substitutions in the EHD1 domains,
advanced imaging techniques, purified proteins, and GST pull-downs. Characterization of the interaction
between EHD1 and VPS35 will further add to the complex upstream regulation of mitochondria fission, which is
essential for the proper mitochondrial function that is lacking in cancer cells. The second aim of this proposal,
to explore a novel role for endocytic proteins in the trafficking of BCL-2 family members and the regulation of
apoptosis, will characterize an entirely novel interaction between components of the retromer complex, VPS35
and VPS26, and components of the BCL-2 family, BCL-xL. To answer fundamental questions about the
relationship between proteins in two pathways that were considered distinct until now, we will use
CRISPR/Cas9 gene-edited cells, confocal and single molecule super-resolution microscopy, co-
immunoprecipitations and apoptosis assays. Overall, this proposal will make a unique contribution to cancer
research by addressing the underlying mechanisms and upstream events that lead to the dysfuncti...

## Key facts

- **NIH application ID:** 9850851
- **Project number:** 5F31CA236290-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Trey M Farmer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $27,683
- **Award type:** 5
- **Project period:** 2018-12-07 → 2020-05-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850851

## Citation

> US National Institutes of Health, RePORTER application 9850851, A Novel Role for Membrane Trafficking in Mitochondrial Homeostasis and Apoptosis (5F31CA236290-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9850851. Licensed CC0.

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