# The Oncogene Activated Mitochondrial Unfolded Protein Response Regulates Senescence Biology

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $597,164

## Abstract

PROJECT SUMMARY
Mitochondria created an evolutionary advantage for eukaryote and metazoan organization, and their impact on
cell biology extends from anabolic and catabolic metabolism to determining the final moments of cell survival by
engaging apoptosis. Throughout the last decade, interest in studying how mitochondria influence cancer cell
biology led our laboratories to identify mechanisms linking oncogenic signaling (i.e., BRAFV600E / NRASG12V ) to
multiple mitochondria-centric processes within malignant cells including altered mitochondrial dynamics,
oxidative phosphorylation, and chemosensitivity. More recently, we focused on exploring how oncogenes
intersect upon mitochondrial biology prior to transformation – which will likely provide molecular details into pre-
malignant cell biology and early stages of disease. We commonly position our studies in the context of melanoma
as we have extensive experience with primary human melanocytes, integrated cohorts of patient RNA-seq
datasets and tissues, and multiple in vitro and in vivo models of early and late disease. For instance, the
introduction of oncogenic signaling (BRAFV600E / NRASG12/Q60) in primary human melanocytes causes rapid
oncogene-induced senescence (OIS), and this tumor-suppressive mechanism is reflected in patients who
present with pre-malignant skin lesions in the clinic. Therefore, the scientific premise for this application is based
on three novel observations: (i) primary human melanocytes expressing oncogenes rapidly expand their
mitochondrial networks during OIS; (ii) this expansion is dictated by the undescribed activation of the ATF5-
dependent mitochondrial unfolded protein response (mtUPR); and (iii) the mtUPR controls the rate and extent of
OIS. While the mtUPR is a fundamental organelle-specific quality control signaling pathway that is essential to
mitigate mitochondrial stress, no literature mechanistically connects oncogenic signaling to mtUPR activation,
melanocyte biology, nor melanoma progression. In our preliminary experiments, we explored biochemical
signaling, mitochondrial responses, cellular gain-of-function / loss-of-function approaches, and hundreds of
patient samples to establish the hypothesis that the oncogene-activated ATF5-dependent mtUPR is a key
signaling pathway that instructs melanocytes during OIS and its escape. In this R01 application, we propose
three complimentary, but distinct, specific aims to examine this hypothesis using melanocytes, numerous models
of early disease, and patient samples. Specific Aim #1: Interrogate the mechanistic relationship between
oncogenic signaling, mtUPR, and OIS. Specific Aim #2: Identify the gene expression programs mediated and
maintained by the mtUPR during OIS and early disease primary melanoma. Specific Aim #3: Define the impact
of mtUPR activation in models of nevi and primary disease.

## Key facts

- **NIH application ID:** 10816599
- **Project number:** 5R01CA271346-02
- **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:** $597,164
- **Award type:** 5
- **Project period:** 2023-04-03 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816599

## Citation

> US National Institutes of Health, RePORTER application 10816599, The Oncogene Activated Mitochondrial Unfolded Protein Response Regulates Senescence Biology (5R01CA271346-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10816599. Licensed CC0.

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