# Administrative Supplements for Equipment Purchases for R35GM129294 Regulation of mitochondrial surveillance

> **NIH NIH R35** · RICE UNIVERSITY · 2024 · $125,829

## Abstract

Summary: Far from the overly simplistic understanding of mitochondria as ‘the powerhouse of the cell’, these
organelles play crucial roles not only in the production of ATP, but also in a wide variety of other biochemical
processes, making mitochondrial function a key determinant of cellular health. Disruption of mitochondrial
homeostasis contributes to a number of chronic diseases, including metabolic, neurodegenerative, and
cardiovascular disorders, cancer, and even aging. Mitochondria undergo constant surveillance and
homeostatic rebalancing to avoid spiraling into a dysfunctional cascade that will inevitably trigger apoptosis or
other cell death pathways. A variety of readouts, including mitochondrial proteostasis and bioenergetics, are
constantly tracked and these inputs are integrated into coherent, retrograde signaling programs that coordinate
gene expression with the nucleus. The most studied of these is the mitochondrial unfolded protein response
(UPRmt), which primarily responds to compromised mitochondrial protein import. Recent results from my lab
have increasingly demonstrated that another key component of mitochondrial surveillance is the ESRE
pathway. The ESRE (ethanol and stress response element) pathway is comprised of evolutionarily-conserved
genes containing a strongly conserved, 11-nucleotide motif (TCTGCGTCTCT) in their promoters. These genes
were first identified by their upregulation during acute ethanol exposure, but we have demonstrated that the
ESRE pathway detects mitochondrial damage, specifically increased mitochondrial reactive oxygen species.
Importantly, compromised ESRE function reduced survival during stress and overexpression of ESRE
machinery extended lifespan in unstressed conditions. Recent discoveries from my lab have identified box C/D
snoRNPs and the Mediator subunit MDT-15/MED15 as critical regulators of ESRE activity. Finally, we have
identified a strong candidate for the transcription factor that binds the ESRE motif.
 Despite our recent progress, critical gaps remain in our understanding of how ESRE contributes to
mitochondrial health. Questions of particular interest include: how is the signal for ESRE activation propagated
to the nucleus once it is detected? Have we correctly identified the transcription factor that binds the ESRE
motif? What is the mechanism used by box C/D snoRNPs to regulate ESRE function? Is MDT-15 acting in a
non-canonical role to regulate ESRE activity? We will continue to use a variety of biochemical, genetic, and cell
biological techniques, supplemented with new ‘omics-based approaches to expand our understanding of this
network and its role in maintaining mitochondrial health. This enhanced understanding will be key to translating
our discoveries into tangible gains in improvements in health across the lifespan.

## Key facts

- **NIH application ID:** 11094505
- **Project number:** 3R35GM129294-06S1
- **Recipient organization:** RICE UNIVERSITY
- **Principal Investigator:** Natasha Kirienko
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,829
- **Award type:** 3
- **Project period:** 2018-09-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11094505

## Citation

> US National Institutes of Health, RePORTER application 11094505, Administrative Supplements for Equipment Purchases for R35GM129294 Regulation of mitochondrial surveillance (3R35GM129294-06S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11094505. Licensed CC0.

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