# Impact of mtDNA Mutations and Transfer on Tumor Growth Dynamics

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $49,556

## Abstract

PROJECT SUMMARY/ABSTRACT
Beyond generating ATP for cellular processes, mitochondria also provide metabolites and signaling factors that
orchestrate cell survival, proliferation, and metabolism. It has been known since the 1930s that most cancer
cells rely mainly on glycolysis even in aerobic conditions. Mitochondria nonetheless remain essential for
metabolic plasticity, the generation of reactive oxygen species (ROS), and nucleotide biosynthesis, all factors
that contribute to metastasis and poor outcomes in cancer. The direct impact of mitochondrial dysfunction,
such as mutations in the mitochondrial genome (mtDNA), has been difficult to study without experimental tools
for editing mtDNA into desired sequences. It remains unknown whether differences in the mtDNA sequence
are sufficient to alter the growth kinetics of a tumor, which is a fundamental lack of understanding with potential
clinical implications. Furthermore, it is unclear whether tumor cells with deleterious mtDNA mutations will
mitigate an impairment in respiration over the natural course of tumor growth, during an epithelial-to-
mesenchymal transition, and with metastasis. Cancer cells lacking endogenous mtDNA (ρ0) have previously
been shown to restore oxidative metabolism by acquiring mitochondria by organelle transfer from non-
malignant cells in the tumor microenvironment. However, this highly artificial system relies upon extreme
selective pressure in ρ0 cancer cells that do not exist in nature. Whether the native mtDNA status in mtDNA-
resident (ρ+) tumor cells changes with tumor progression has not been determined.
To address this key question, it is necessary to generate tumor cells with different known mtDNA mutations in
an isogenic nuclear background. Members of my thesis lab developed an in vitro method for permanently
transferring isolated mitochondria into ρ0 recipient cells of choice, enabling generation of cancer clones with
specific mtDNA mutations and identical nuclear genomes. In Aim 1 studies, I will use B16 mouse melanoma
and 4T1 mammary cancer cells as the nuclear backgrounds and generate cancer cells with a panel of wild-
type and mutant mtDNA sequences. I will quantify how these mutations alter their metabolism, ROS levels,
and invasive capacities in vitro. In Aim 2, I will inject these cells, along with ρ+ and ρ0 controls, into mice
subcutaneously and quantify how mtDNA mutations affect kinetics of tumor growth and metastasis. In Aim 3, I
will purify tumor cells from local and disseminated disease and analyze changes in mtDNA sequences and
tumor cell function following metastasis. Due to differences in respiratory capacities and metabolic profiles
between cells containing different mtDNA, I anticipate growth rates and rates of metastasis will vary between
lines even before potential mitochondrial acquisition from the normal microenvironment. Understanding the
dependence of cancer cells on their mtDNA and whether mtDNA is exchanged in a ρ+ tumor cell setting w...

## Key facts

- **NIH application ID:** 10439441
- **Project number:** 5F30CA257682-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Amy Katherine Yu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $49,556
- **Award type:** 5
- **Project period:** 2021-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439441

## Citation

> US National Institutes of Health, RePORTER application 10439441, Impact of mtDNA Mutations and Transfer on Tumor Growth Dynamics (5F30CA257682-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10439441. Licensed CC0.

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