# Mechanistic Elucidation of Mitochondrial Stress Response in Human Cells

> **NIH NIH R35** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2024 · $416,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Mitochondria play essential roles in eukaryotic cells. However, they are often subject to stress originated from
various sources, both intrinsic and extrinsic. In response to such stress, cells activate a diverse array of stress
response mechanisms collectively known as the mitochondrial stress response, aimed at restoring mitochondrial
homeostasis and preserving overall cellular fitness. Our recent work has uncovered a key mitochondrial stress
response pathway involving the integrated stress response (ISR), a cellular strategy for coping with diverse
stress conditions. Despite distinct triggering mechanisms, all the ISR pathways converge on the phosphorylation
of eIF2a by four stress-specific kinases (PKR, GCN2, HRI and PERK). This phosphorylation event leads to an
attenuation of global protein synthesis while upregulating the expression of stress response transcription factor
like ATF4. Our research has revealed an OMA1-DELE1-HRI signaling cascade as a distinct link between
mitochondrial stress and the ISR, offering a unique therapeutic target for manipulating the ISR in disorders
associated with mitochondrial dysfunction. However, we currently lack a comprehensive understanding of how
cells integrate mitochondrial stress programs to maintain a homeostatic mitochondrial network. The long-term
goal of our lab is to comprehensively elucidate molecular and cellular mechanisms of the mitochondrial stress
response spanning from the molecular mechanisms of stress sensing and transmitting to the ultimate outcomes.
Recent findings by us and others highlighted critical roles of protein trafficking in sensing and relaying
mitochondrial stress. By leveraging reporter-based assays, CRISPR screens, reconstituted cell-free assays and
proteomics approaches, a primary objective of our lab is to elucidate the molecular mechanisms governing
protein dynamics during mitochondrial stress. While emerging as a primary mitochondrial stress response under
various stress conditions in a wide range of cell types, there remains a significant gap in understanding how the
OMA1-DELE1-HRI-mediated ISR integrates with other mitochondrial stress response programs to maintain
mitochondrial homeostasis. Another key objective of our lab is to systematically elucidate the intricate
mechanisms involved in maintaining a homeostatic mitochondrial network. Considering that mitochondrial
dysfunction is a major hallmark of numerous diseases such as primary mitochondrial diseases and
neurodegenerative diseases, our mechanistic investigations into the mitochondrial stress response are
anticipated to significantly advance our understanding of these pathological conditions and will potentially identify
novel therapeutic targets to mitigate their impacts.

## Key facts

- **NIH application ID:** 10940682
- **Project number:** 1R35GM155240-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Xiaoyan Guo
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $416,250
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940682

## Citation

> US National Institutes of Health, RePORTER application 10940682, Mechanistic Elucidation of Mitochondrial Stress Response in Human Cells (1R35GM155240-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10940682. Licensed CC0.

---

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