# The role of heteroplasmic mitochondrial DNA mutations on tumorigenesis and metabolism

> **NIH NIH F31** · CORNELL UNIVERSITY · 2020 · $31,800

## Abstract

Project Summary/Abstract
 The electron transport chain (ETC) activity in mammalian cells is necessary for survival and
proliferation. The ETC is composed of ~100 subunits mostly encoded in the nuclear genome, but 13 essential
subunits are in the mitochondrial genome (mtDNA). Accumulation of mutations in the mtDNA can lead to
severe genetic defects and cell death. Interestingly, we and other groups have found the occurrence of loss-of-
function (LOF) mtDNA mutations across a variety of cancer types at high heteroplasmy. Heteroplasmy is
defined as the proportion of mtDNA with a specific mutation over the total number of mtDNA. Furthermore,
there is an enrichment for these LOF mutations suggesting that they are positively selected. Despite their
prevalence, it is unclear whether these mutations have functional roles in cancer progression or are simply
passenger mutations as the study of mtDNA mutations is stymied by the lack of methods to genetically modify
the mtDNA. Here, I aim to test the hypothesis that heteroplasmic mtDNA mutations have functionally critical
roles in tumorigenesis.
 In our preliminary work, we conducted single-cell RNAseq (scRNAseq) on Cal62, an anaplastic thyroid
cancer cell line with three mtDNA loss-of-function (LOF) mutations. Using these data, I performed differential
expression analysis between cells with high (0.8-1) and low (0-0.2) heteroplasmy levels which revealed an
Epithelial-Mesenchymal-Transition (EMT) gene signature enriched in highly heteroplasmic cells. This raises
the possibility that mtDNA mutations may result in a more invasive phenotype by impacting gene expression.
In this proposal, I will elucidate the association between heteroplasmy and the EMT by creating an isogenic
mtDNA mutant Cal62 cells and determine the impact of mtDNA mutations on cellular metabolism and growth.
 In this proposal, I will build upon our preliminary work to determine the association between mtDNA
mutations and the EMT. In Aim1, I will identify transcripts that stratify cells of different heteroplasmy levels
using scRNAseq in order to create isogenic mtDNA mutant cell lines. In Aim2, I will use the isogenic cell lines
to determine the impact of mtDNA mutations on cellular metabolism and growth. I anticipate that these studies
will determine: 1) the impact of mtDNA mutations on the cellular transcriptome and 2) the association of these
mutations to cellular invasiveness. This work will be completed in the laboratory of Dr. Kvanç Birsoy with the
co-advisement of Dr. Andrew Clark at Rockefeller and Cornell University, respectively. The training plan
outlined in this proposal is designed to best prepare me for a career as an independent scientist following my
post-doctoral training.

## Key facts

- **NIH application ID:** 10142807
- **Project number:** 7F31CA247528-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Konnor La
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,800
- **Award type:** 7
- **Project period:** 2020-04-29 → 2020-12-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142807

## Citation

> US National Institutes of Health, RePORTER application 10142807, The role of heteroplasmic mitochondrial DNA mutations on tumorigenesis and metabolism (7F31CA247528-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10142807. Licensed CC0.

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