# Understanding the effects of mitochondrial fission disruption during early cortical development

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $34,269

## Abstract

Summary
With the advent of exome sequencing, a growing number of children are being identified with de novo loss of
function mutations in the large GTPase essential for mitochondrial fission - Dynamin Related Protein 1 (DRP1);
these mutations result in severe neurodevelopmental phenotypes such as developmental delay, optic atrophy,
and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to
the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in
different domains of DRP1 uniquely disrupt this process. F-actin and the endoplasmic reticulum (ER) form a
complex to prime the mitochondria for fission by pre-constricting the mitochondrial membrane prior to formation
of DRP1 oligomers. The effect of DRP1 mutations on protein interactions with F-actin and the ER has never
been studied in cell types of the developing cortex. This proposal focuses on testing the mechanism of DRP1
dysfunction both on protein interactions at sites of fission as well as downstream effects on cortical neuron
differentiation and maturation. We aim to approach these gaps by leveraging the power of induced pluripotent
stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model cell-fate changes
associated with early cortical development. We will functionally assess the capacity for these iPSCs with mutant
DRP1 to adopt a neural progenitor fate and progress to active cortical neurons using quantitative analysis of
neurite outgrowth and branching, calcium transient recording, and synchronous synaptic firing. To understand
how mutant forms of DRP1 interact with F-actin and the ER during fission, we will use live super-resolution
Airyscan microscopy paired with in-cell immunoprecipitation to capture changes in the assembly and
disassembly of this fission machinery. Successful completion of these aims will improve our understanding of
the role of mitochondrial fission during cortical development and at which stages of this process perturbations
become highly pathogenic. Furthermore, these results could help shed light on variable patient symptoms and
outcomes based on specific DRP1 mutations, possibly leading to individualized therapeutics for mitochondrial
disease.

## Key facts

- **NIH application ID:** 10700890
- **Project number:** 5F31NS129296-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Tierney Baum
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,269
- **Award type:** 5
- **Project period:** 2022-12-05 → 2025-06-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10700890

## Citation

> US National Institutes of Health, RePORTER application 10700890, Understanding the effects of mitochondrial fission disruption during early cortical development (5F31NS129296-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10700890. Licensed CC0.

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