# The impact of mitochondrial and peroxisomal fission dynamics on metabolic signaling during corticogenesis.

> **NIH NIH K00** · BROAD INSTITUTE, INC. · 2024 · $86,508

## Abstract

PROJECT SUMMARY/ABSTRACT
Mitochondria are dynamic signaling organelles that constantly undergoes fission (fragmentation) and fusion
(elongation) to adapt its structure to the demands of the cell. DRP1 (dynamin-related protein 1) is a GTPase that
plays a crucial role in mitochondrial fission. Patients with de novo heterozygous missense mutations in the gene
that encodes DRP1, DNM1L, present with neurodevelopmental symptoms. To interrogate the molecular
mechanisms by which DRP1 mutations cause neurodevelopmental defects, we are utilizing patient-derived
fibroblasts and iPSC-derived models from patients with mutations in different domains of DRP1 who present with
clinically disparate conditions. The G32A mutation lies in the GTPase domain of DRP1 and is associated with
microcephaly. The R403C mutation lies in the stalk domain of DRP1 and causes progressively severe epilepsy.
Specific Aim 1 presents the progress thus far to uncover the impact of DRP1 mutations on mitochondrial structure
and metabolic function using patient-derived fibroblasts. Patient cells display elongated mitochondrial structure
and impaired coupling efficiency of the electron transport chain (ETC). Specific Aim 2 (the F99 phase of this
proposal) will explore the consequences of these findings in neurodevelopment using patient-derived induced
pluripotent stem cell (iPSC) models: three-dimensional cerebral organoids and two-dimensional neural
progenitor cultures. Confocal imaging and mass cytometry (CyTOF) will be used to determine if patient mutations
lead to change of cell fate in early corticogenesis. Further, multi-electrode array (MEA) technology will be
leveraged to examine the development of neuronal network activity in patient-derived brain organoids.
Understanding the mechanism by which these mutations cause neurological pathology will give insight into the
role of mitochondrial dynamics in neurodevelopment. Specific Aim 3 (the K00 phase of this proposal) will develop
the applicant into an independent academic researcher investigating the interactions between metabolic
signaling and neurodevelopment. The K00 phase will provide the applicant with training in metabolic analysis
using carbon tracing and in vitro biochemical assays as well as the professional development and networking
necessary to run an independent research laboratory. Overall, the work outlined in this proposal will equip the
candidate with both the technical expertise and professional skills to make great strides in the field of metabolism
in neurodevelopment.

## Key facts

- **NIH application ID:** 10702075
- **Project number:** 4K00NS125829-03
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Gabriella Lou Puig Robertson
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $86,508
- **Award type:** 4N
- **Project period:** 2021-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10702075

## Citation

> US National Institutes of Health, RePORTER application 10702075, The impact of mitochondrial and peroxisomal fission dynamics on metabolic signaling during corticogenesis. (4K00NS125829-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10702075. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*