# Nuclear-mitochondrial co-regulation during mitochondrial biogenesis

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $334,485

## Abstract

PROJECT SUMMARY/ABSTRACT
Defects in the assembly and maintenance of mitochondrial oxidative phosphorylation (OXPHOS) machinery
lead to a range of degenerative illnesses, including diabetes, cancer, and neurodegenerative diseases.
OXPHOS complexes are encoded on both the nuclear and mitochondrial genomes, so their biogenesis
requires the precise coordination of gene regulatory mechanisms across genomes. To this end, mitochondrial
biogenesis and stress response programs involve the simultaneous transcriptional upregulation of nuclear-
encoded OXPHOS genes and mitochondrial gene expression factors. These transcriptional programs are
thought to facilitate nuclear-mitochondrial balance, where mitochondrial-encoded OXPHOS subunits assemble
in stoichiometric ratios with their nuclear-encoded counterparts. We recently observed in Saccharomyces
cerevisiae that transcription regulation of nuclear-encoded and mitochondrial-encoded OXPHOS subunits are
not coordinated during carbon source adaptation. Instead, the cell synchronizes the translational regulation of
OXPHOS subunits across compartments. Whether synchronized translation is a widespread response remains
unknown. The goal of this proposal is to determine how mitochondrial and nuclear genomes are co-regulated,
particularly during protein synthesis, throughout mitochondrial biogenesis and stress response programs. As
an extension of our recent work in yeast, Aim 1 will investigate whether synchronous translation programs
occur across a range of environmental and mitochondrial stress adaptation programs. We will also determine
how the synchronous translation regulation occurs by determining the role of key mitochondrial translation
regulators in the dynamic regulation of OXPHOS genes during carbon source adaptation. This will be done
using our mitochondrial ribosome profiling approach and cytosolic ribosome profiling to measure protein
synthesis and RNA-seq to measure global transcription. In Aims 2 and 3, we extend our studies to human
cells through re-engineering ribosome profiling to robustly capture human mitochondrial translation. To test the
approach, we will investigate how a putative translation activator, TACO1, impacts human mitochondrial
translation. We will investigate nuclear-mitochondrial co-regulation after acute mitochondrial stress induced by
chemical inhibition of OXPHOS complexes, mimicking OXPHOS dysfunction in disease processes. Finally, we
will investigate mitochondrial and nuclear gene expression programs during the in vitro differentiation of iPS
cells to cardiomyocytes, when extensive mitochondrial biogenesis occurs. Determining the regulation and the
extent of nuclear-mitochondrial co-regulation will provide critical insight towards understanding how
imbalanced production of OXPHOS subunits transpires in disease states.

## Key facts

- **NIH application ID:** 9996717
- **Project number:** 5R01GM123002-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Lee Stirling Churchman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $334,485
- **Award type:** 5
- **Project period:** 2017-08-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996717

## Citation

> US National Institutes of Health, RePORTER application 9996717, Nuclear-mitochondrial co-regulation during mitochondrial biogenesis (5R01GM123002-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9996717. Licensed CC0.

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