# Exploiting mitochondrial heteroplasmy for cancer chemotherapy

> **NIH NIH R01** · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · 2021 · $390,000

## Abstract

Project Summary
Title: Exploiting mitochondrial heteroplasmy for cancer chemotherapy
Roughly a third of patient cancers are heteroplasmic -- that is, individual cells harbor a mixture of genetically
distinct mitochondrial genomes -- and a substantial fraction of these bear severe loss-of-function mutations
affecting genes necessary for respiration. These mutations appear to be passengers rather than drivers of
tumorgenesis, but our lab recently discovered that they can render cancer cell lines and xenografts more
vulnerable to biguanides, mitochondrial inhibitors used to treat type 2 diabetes. Since heteroplasmy is
relatively rare in normal tissues, these findings suggest that mitochondrial inhibitors may have a therapeutic
window for treating heteroplasmic cancers, but specifically when and how this heteroplasmy may be
exploited for treatment remains poorly understood. Additionally, our work showed that heteroplasmy is a
reversible genetic defect, since heteroplasmic cells generally still contain wild-type copies of the
mitochondrial genome, and that partial reversion is a route to drug resistance. This reduction of
heteroplasmy is not a simple mutational processes, and its mechanisms are unknown. The proposed work
aims to fill both of these gaps in current knowledge with a systematic study of how heteroplasmy affects
susceptibility to a variety of relevant inhibitors and how these inhibitors may drive changes in heteroplasmy
leading to drug resistance.

## Key facts

- **NIH application ID:** 10215430
- **Project number:** 5R01CA219859-05
- **Recipient organization:** WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
- **Principal Investigator:** JONATHAN S. WEISSMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215430

## Citation

> US National Institutes of Health, RePORTER application 10215430, Exploiting mitochondrial heteroplasmy for cancer chemotherapy (5R01CA219859-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10215430. Licensed CC0.

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