# Chronic Mitochondrial Division and Melanoma: Mechanism, Prognosis, and Therapy

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $467,789

## Abstract

PROJECT SUMMARY
The impact of mitochondrial biology on human cancers is broad because these organelles are critical regulators
of metabolism, proliferation, metastasis, and cell death. Indeed, mitochondrial aberrations are common in
multiple cancer types – not only do mitochondrial dysfunctions correlate with disease pathogenesis, but aberrant
mitochondria also negatively impact upon chemotherapeutic success. Within a cell, mitochondrial homeostasis
is maintained by a process referred to as “mitochondrial dynamics”, which is essential for efficient ATP
generation, mitochondrial metabolites/substrates distribution, and mitochondrial DNA (mtDNA) integrity.
Homeostatic mitochondrial dynamics result from the cumulative nature of complementary cycles of mitochondrial
division and fusion. Work from my laboratory demonstrates: (1) the mitochondrial division machinery is essential
for cellular transformation, (2) mitochondrial division is chronically activated in RAS-transformed murine cells
and human cancer lines harboring oncogenic mutations within the MAPK pathway, (3) chronic mitochondrial
division is sufficient to initiate mitochondrial dysfunction and cancer cell metabolism, and (4) FDA-approved
targeted therapies that inhibit oncogenic MAPK signaling turn off the mitochondrial division machinery. While the
above studies link chronic mitochondrial division to cancer biology, mechanistic explanations for how chronic
mitochondrial division promotes organelle dysfunction and cancer phenotypes are scarce. In this R01
application, our goals are to (1) provide key mechanistic details into the process and contributions of
mitochondrial dysfunction during oncogenic transformation, and (2) develop novel translational tools focused on
the detection and inhibition of chronic mitochondrial division to enhance cancer prognosis and treatment. As our
expertise and resources are in dermatology, we will focus on melanoma. The presence of mtDNA mutations and
mitochondrial aberrations in cancer have been described for decades, but the molecular events that drive these
changes and their impact on cancer biology remain speculative. To address this knowledge gap, we recently
completed an unbiased screen using normal melanocytes and melanoma cell lines to understand how chronic
mitochondrial division impacts on mitochondrial function, and identified that loss-of-function mtDNA mutations
are essential for cancer cell metabolism, proliferation, and tumorigenesis. We hypothesize that oncogene-
induced chronic mitochondrial division promotes mtDNA mutations and organelle heterogeneity to instigate
transformation. Based on our data, chronic mitochondrial division is an early event during melanomagenesis,
and provides strong prognostic value and therapeutic potential. This project emerged following years of effort to
identify how chronic mitochondrial division impacts cancer mechanisms, prognosis, and treatment.

## Key facts

- **NIH application ID:** 10853103
- **Project number:** 5R01CA267696-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jerry Edward Chipuk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $467,789
- **Award type:** 5
- **Project period:** 2022-07-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853103

## Citation

> US National Institutes of Health, RePORTER application 10853103, Chronic Mitochondrial Division and Melanoma: Mechanism, Prognosis, and Therapy (5R01CA267696-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10853103. Licensed CC0.

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