# Defining Endoplasmic Reticulum Stress-Development Mitochondria Remodeling

> **NIH NIH RF1** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $2,356,233

## Abstract

PROJECT SUMMARY
Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are intricately linked in the onset and
pathogenesis of numerous neurodegenerative diseases such as Alzheimer’s disease (AD) and related
tauopathies including progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD). However, the
pathologic relationship between ER stress and mitochondrial dysfunction in these diseases is currently poorly
defined. Clinical, genetic, and biochemical evidence shows that imbalanced signaling through the PERK arm of
the unfolded protein response (UPR) contributes to the neuronal dysfunction associated with many
neurodegenerative diseases including those listed above. PERK integrates transcriptional and translational
signaling to promote adaptive remodeling of mitochondrial proteostasis and function in response to acute ER
stress. However, in response to chronic ER stress, PERK initiates apoptosis through complex mechanisms that
involve mitochondrial dysfunction. This leads to the intriguing question: ‘How does PERK differentially regulate
protective and pathologic aspects of mitochondrial function in response to varying levels of ER stress?’. We
demonstrated that PERK-dependent translation attenuation promotes adaptive mitochondrial elongation in
response to acute ER insults. Here, we will show that this change in mitochondrial morphology corresponds to
PERK-dependent regulation of phospholipids within mitochondrial membranes. Intriguingly, changes in
phospholipids are implicated in the pathogenesis of multiple neurodegenerative diseases. Further, mitochondrial
phospholipids are key regulatory determinants for diverse aspects of mitochondrial biology including morphology,
oxidative phosphorylation, and apoptosis. Here, we test the hypothesis that PERK-dependent regulation of
mitochondrial phospholipids promotes adaptive remodeling of mitochondrial membranes during ER
stress and that imbalances in this regulation contributes to the pathologic mitochondrial dysfunction
observed during neurodegeneration. Using a combination of biochemical, metabolomic, and imaging-based
approaches, we will define the molecular basis for PERK-dependent regulation of mitochondrial phospholipids
and demonstrate the importance of this regulation in dictating mitochondrial morphology, cristae ultrastructure,
and function in response to ER stress. Through these efforts, we will identify PERK-dependent regulation of
mitochondrial phospholipids as a mechanism to adapt mitochondria in response to acute ER stress. Further, we
will show that chronic PERK signaling induces pathologic alterations to mitochondrial phospholipids that
contributes to the mitochondrial dysfunction associated with neurodegeneration. Collectively, our results will
establish PERK-dependent remodeling of mitochondrial membrane phospholipids as a key determinant in
dictating mitochondrial function in response to varying levels of ER stress. Further, our work will reveal new
insights i...

## Key facts

- **NIH application ID:** 10537152
- **Project number:** 1RF1NS125674-01A1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Rockland Luke Wiseman
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,356,233
- **Award type:** 1
- **Project period:** 2022-08-20 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537152

## Citation

> US National Institutes of Health, RePORTER application 10537152, Defining Endoplasmic Reticulum Stress-Development Mitochondria Remodeling (1RF1NS125674-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10537152. Licensed CC0.

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