# Mitophagy in Tumor Microenvironment

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $380,062

## Abstract

Abstract
Mitophagy is the process of selective removal of damaged mitochondria via autophagy. However, the impact of
mitophagy in the tumor microenvironment (TME) remains unclear. Our preliminary data suggest that mitophagy
plays a novel role in the suppression of pancreatic tumorigenesis. Using mouse models of spontaneous
pancreatic cancer, we show that depletion of Pink1 and Park2, two core mediators of mitophagy in mammalian
cells, accelerates mutant Kras-driven pancreatic cancer development. Mechanistically, mitophagy deficiency
increases SLC25A37- and SLC25A28-dependent mitochondrial iron accumulation, which leads to the HIF1A-
dependent Warburg effect and AIM2-dependent inflammasome activation in the TME. AIM2 inflammasome-
mediated HMGB1 release further induces expression of the immune checkpoint protein CD274/PD-L1.
Consequently, pharmacological administration of mitochondrial iron chelator, anti-HMGB1 antibody, or genetic
depletion of Hif1a or Aim2 in pink1-/- and park2-/- mice confers protection against mutant Kras-driven pancreatic
tumorigenesis. Importantly, high AIM2 expression is associated with poor prognosis in patients with pancreatic
cancer. These exciting findings support our central hypothesis that mitophagy suppresses pancreatic
tumorigenesis through control of the mitochondrial iron-dependent TME. To test this hypothesis, we will exploit
molecular, cellular, and animal models to pursue the following aims. Aim 1: Identify the mechanisms of mitophagy
deficiency-mediated mitochondrial iron accumulation in the TME. Aim 2. Identify the mechanisms of
mitochondrial iron accumulation-mediated chronic inflammation in the TME. Aim 3. Identify the mechanisms of
mitochondrial iron accumulation-mediated immunosuppression in the TME. The completion of these exciting
studies will uncover a previously underappreciated role for mitophagy in modulating mitochondrial iron
metabolism in the TME and suggest targeting these events for tumor therapy.

## Key facts

- **NIH application ID:** 10018809
- **Project number:** 5R01CA160417-08
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Daolin Tang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,062
- **Award type:** 5
- **Project period:** 2012-09-10 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018809

## Citation

> US National Institutes of Health, RePORTER application 10018809, Mitophagy in Tumor Microenvironment (5R01CA160417-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018809. Licensed CC0.

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