# Coordinated Regulation of Mitochondrial Surveillance

> **NIH NIH R35** · RICE UNIVERSITY · 2021 · $384,615

## Abstract

Summary: Due to their central role in a variety of metabolic functions (and their propensity for self-inflicted
damage from reactive oxygen species) mitochondria are an important target for homeostatic surveillance
pathways. Mitochondrial dysfunction and surveillance defects are increasingly linked to human health problems,
including metabolic, neurological, and cardiovascular diseases, cancer, and even aging. Recent discoveries have
demonstrated that several different programs exist for monitoring mitochondrial function and health, including the
mitochondrial unfolded protein response (UPRmt), the ethanol and stress response element (ESRE) surveillance
pathway, and the autophagic degradation of mitochondrial material. Recent discoveries have suggested that
mitochondrial stress triggers a bidentate resolution mechanism, wherein the expression of chaperones and other
stress-mitigating factors are upregulated while general cell translation is dampened in an effort to restore
homeostasis before mitochondrial turnover becomes necessary.The goal of this research program is to gain a
better understanding of these pathways, both alone and in interaction with each other. In addition, their
interactions with core cellular machinery, such as protein translation, are also of particular interest, especially as it
relates to the paradigm of resolving mitochondrial stress. Our first goal uses a combination of genetic and
biochemical methods to identify the mechanisms used by the ESRE pathway to mediate adaptive stress responses.
There are critical gaps in our understanding of the fundamental mechanisms of ESRE network function, such as the
identity of the transcription factors that bind the ESRE nucleotide motif element, how this pathway is activated,
and how it promotes resistance to mitochondrial damage. Our second goal is to study a novel ribosomal protein
modification, which is a key aspect of the ESRE response, and shapes the response to mitochondrial damage. Our
analysis will determine the conditions that activate this modification, whether it can be reversed, the role it plays in
controlling protein translation, and its relationships with mitochondrial surveillance. To answer these questions, we
will use CRISPR-based genetics, in vitro biochemical, and quantitative mass spectrometry approaches. Third, a
broader goal focuses on the relationships between ESRE, the UPRmt, other mitochondrial surveillance networks and
mitophagy. For example, we will explore the events that trigger each of these surveillance programs and elucidate
the interactions and interdependence of these pathways. We are interested in determining whether cells activate
these pathways in an autonomous fashion, or whether signals from one tissue can activate defense networks in
other cell types. We are particularly interested in the events leading up to activation of mitochondrial turnover
(i.e., mitophagy), since it represents an irreversible commitment to profound cellular changes. We w...

## Key facts

- **NIH application ID:** 10240482
- **Project number:** 5R35GM129294-04
- **Recipient organization:** RICE UNIVERSITY
- **Principal Investigator:** Natasha Kirienko
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,615
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240482

## Citation

> US National Institutes of Health, RePORTER application 10240482, Coordinated Regulation of Mitochondrial Surveillance (5R35GM129294-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10240482. Licensed CC0.

---

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