# The role of mito-nuclear communication in the adaptation to mitochondrial dysfunction and stress resistance

> **NIH NIH R35** · UNIVERSITY OF VIRGINIA · 2024 · $168,170

## Abstract

PROJECT SUMMARY/ABSTRACT
 Interactions between mitochondrial (mtDNA) and nuclear (nDNA) genomes are essential for
maintaining mitochondrial and cellular functions. However, an age- and disease-associated increase of
heteroplasmic mtDNA (the presence of different mtDNA haplotypes) creates an inter-genomic mismatch that
perturbs mitonuclear interaction efficiency. Disrupted mitonuclear interaction results in mitochondrial
dysfunction, reduced organismal fitness, and initiation of various stress that has been associated with a
plethora of many human diseases, such as Huntington's disease, Leber's hereditary optic neuropathy, and
type 2 diabetes mellitus. In response to disrupted mitonuclear interactions, cells activate stress response
pathways to remodel gene expression and metabolism, thereby maintaining mitochondrial function and
alleviating cellular stress. However, a detailed molecular understanding of mitonuclear mechanisms linking
activation of stress response pathways for maintaining mitochondrial function and stress resistance has been
understudied, representing a significant knowledge gap. I hypothesize that distinct mismatched mitonuclear
genomes maintain coordination of mitochondrial status with various stress response pathways to alleviate
harmful consequences of suboptimal mitonuclear interactions. To test this hypothesis, we developed a novel
yeast mitonuclear exchange model (cytoductants) by combining more than 100 mtDNA genotypes onto the
same nDNA genetic background, thereby generating an elegant system with various degrees of perturbation in
mitonuclear interaction and altered mitochondrial function. Overall, the main goal of our research is to
mechanistically understand how perturbations in mitonuclear interaction are transduced into biological effects.
My laboratory will build and sustain three research projects to accomplish this goal. We will first test the
hypothesis that understanding mitonuclear communication at molecular level will uncover distinct mitonuclear
responses to perturbed mitonuclear interactions. (Project 1). Secondly, we will identify the crosstalk between
stress response pathways and their downstream effectors in protecting cells from various stress under the
condition of perturbed mitonuclear interaction. Further, we will determine whether a specific type of stressor
determines the specificity of the response or not (Project 2). Finally, with an innovative cell engineering
approach, we will investigate the hypothesis that balancing cellular energy hemostasis can mitigate the effect
of disrupted mitonuclear interaction (Project 3). The proposed research is significant because it will uncover
how cells respond to disrupted mitonuclear interactions to maintain cellular homeostasis. Since many
mitochondrial diseases are carried in heteroplasmy, this basic research into the maintenance of mitonuclear
interaction will likely identify modulators of efficient mitochondrial interaction. It might be targeted
pharmacolo...

## Key facts

- **NIH application ID:** 11260722
- **Project number:** 7R35GM150858-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Alaattin Kaya
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $168,170
- **Award type:** 7
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11260722

## Citation

> US National Institutes of Health, RePORTER application 11260722, The role of mito-nuclear communication in the adaptation to mitochondrial dysfunction and stress resistance (7R35GM150858-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11260722. Licensed CC0.

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