# (PQ5) Consequences of imbalanced mitophagy and mitochondrial biogenesis in cancer

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $319,238

## Abstract

Project Summary
The proposed research tests the novel concept that mitophagy and mitochondrial biogenesis are
coordinately regulated to promote both turnover of old mitochondria but also to facilitate rapid and
wholesale re-programming of mitochondria in response to stress. Furthermore, we suggest that this
regulated coupling of mitophagy and mitochondrial biogenesis is disrupted in cancers by oncogenic
signaling resulting in increased mitochondrial mass and incomplete metabolic switching in response to
stress. Finally, we identify novel chemical regulators of these processes that may ultimately be
exploited for cancer therapy. These ideas are tested in the aims set out below.
In Aim 1, we set out to measure the kinetics and interdependence of mitophagy and mitochondrial
biogenesis in normal breast epithelia compared to a panel of breast cancer cells, to allow us to identify
pathways and commonalities in how these two processes are controlled. We also use proteomic
approaches to define changes in mitochondria in response to stress and as a function of intact
mitophagy or mitochondrial biogenesis. Finally, we develop approaches to “track” mitochondria to
determine whether there are “stem” mitochondria that are resistant to mitophagy, to which new
mitochondrial protein mass is preferentially added.
In Aim 2, we leverage data from normal cells examined in Aim 1, and determine how these pathways
and signaling events are altered in different human breast cancer cell lines and in primary human
breast cancers. We examine whether increased mitochondrial mass is linked to defective mitophagy,
increased biogenesis or potentially uncoupling of these process and whether this in turn is associated
with specific oncogenic lesions. We use inducible c-Myc systems to address how oncogenic activity
driving biogenesis affects coordination with mitophagy and overall mitochondrial mass and whether this
plays into a tumor suppressor role for mitophagy and a tumor promoting role for biogenesis.
In Aim 3, we identify of FDA approved drugs that promote tumor cell killing by preventing removal of
damaged mitochondria, or the generation of new healthy mitochondria, with limited effects on normal
cells. Since these drugs are already FDA approved for other purposes, they could be translated to the
breast cancer clinic rapidly (within 2-5 years) tailored to their new role as inhibitors of mitochondria
housekeeping, rapid tumor cell killing and promoting recurrence-free survival.
Overall, we expect to provide insight to novel mechanisms of tumorigenesis that relate to control of
mitophagy and mitochondrial biogenesis in such a way that may explain the heterogeneity in
mitochondrial mass detected in primary human breast cancers.!

## Key facts

- **NIH application ID:** 10103786
- **Project number:** 5R01CA216242-05
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** KAY F MACLEOD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $319,238
- **Award type:** 5
- **Project period:** 2017-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10103786

## Citation

> US National Institutes of Health, RePORTER application 10103786, (PQ5) Consequences of imbalanced mitophagy and mitochondrial biogenesis in cancer (5R01CA216242-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10103786. Licensed CC0.

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