# Metabolic control of mitonuclear balance for OXPHOS protein biogenesis

> **NIH NIH F32** · HARVARD MEDICAL SCHOOL · 2024 · $73,828

## Abstract

PROJECT SUMMARY
The coordinated expression of the nuclear and the mitochondrial genomes is critical for mitochondrial function;
yet, what regulates this process in humans is unclear. This coordination, termed mitonuclear balance, is
especially important for the biogenesis of the mitochondrial oxidative phosphorylation (OXPHOS) complexes,
which are composed of >90 proteins encoded by both the nuclear and the mitochondrial genomes. A significant
challenge in gene regulation is the synthesis of these complexes, as the two physically separate genomes must
coordinate their gene expression programs to produce the correct ratios of the subunits, ensuring proper complex
assembly and function. The imbalanced production of OXPHOS subunits can be detrimental to the cell; orphan
subunits and assembly intermediates lead to the accumulation of reactive oxygen species, which can lead to
mitochondrial dysfunction and mitochondrial disorders, including neurodegeneration and metabolic conditions.
Using a FACS-based CRISPR screen developed by our lab, we recently discovered that metabolism-related
factors play a role in the balanced expression of OXPHOS complex IV subunits in human cells, thus linking
certain aspects of cellular metabolism to mitonuclear balance. The overall objective of this proposal is to identify
novel factors that regulate OXPHOS protein biogenesis and determine their mechanism of regulation. The
central hypothesis is that diverse aspects of metabolism influence the expression of the two genomes across
compartments for balanced OXPHOS protein synthesis. In Aim 1, I will investigate the function of MMADHC, a
protein involved in vitamin B12 metabolism, and which is a putative regulator of complex IV subunit synthesis. I
will determine the role of MMADHC on OXPHOS protein biogenesis and mitochondrial health, its impact on
transcription and translation of OXPHOS subunits, and its role in establishing critical metabolite pools. In Aim 2,
I will use our CRISPR/FACS screen to individually knock-out ~3000 metabolism-related genes, and identify
genes whose loss leads to imbalanced expression of dual-origin subunits of complex I. I will determine the gene
regulatory roles of the top hits, and whether they are regulators of complex I subunits specifically, or of OXPHOS
complexes in general. I will conduct the proposed research at Harvard Medical School, in the lab of Dr. L. Stirling
Churchman, who is an expert on nuclear and mitochondrial gene expression and who has developed a variety
of sequencing technologies for studying the different levels of gene regulation. This proposal is part of a
comprehensive professional training plan to prepare me for a career as an independent research scientist
investigating coordination of gene expression across the nucleocytosolic and mitochondrial compartments, and
its dysfunction in disease and development. With the completion of the proposed work, the results will uncover
general pathways involved in mitonuclear bala...

## Key facts

- **NIH application ID:** 10997686
- **Project number:** 1F32GM156063-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Ana-Maria Raicu
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997686

## Citation

> US National Institutes of Health, RePORTER application 10997686, Metabolic control of mitonuclear balance for OXPHOS protein biogenesis (1F32GM156063-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10997686. Licensed CC0.

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