Language

English

Publication Date

4-9-2025

Journal

bioRxiv

DOI

10.1101/2025.04.03.647049

PMID

40291669

PMCID

PMC12026588

PubMedCentral® Posted Date

4-9-2025

PubMedCentral® Full Text Version

Pre-Print

Abstract

Purpose: Ultra-high dose rate (>40 Gy/s, FLASH) radiation therapy (RT) provides equivalent tumor control while reducing normal tissue toxicity relative to conventional dose rate (CONV) RT. However, the mechanisms underlying the observed FLASH effect are unknown. We hypothesized that the preservation of mitochondrial integrity in nontumorigenic cells by FLASH RT could be a key factor in reducing normal tissue toxicity and improving overall treatment outcomes.

Methods: We examined mitochondrial health and function after CONV and FLASH in vitro, ex vivo, and in vivo through assays of metabolic flux, mitochondrial membrane potential, mitochondrial reactive oxygen species (ROS), mitochondrial DNA damage and copy number, mitochondrial morphology, and tumor growth and survival.

Results: In in vitro assays, murine pancreatic cancer (PDAC) cells showed evidence of equal mitochondrial damage in response to CONV and FLASH, but nontumorigenic pancreatic cells were spared by FLASH. These results were recapitulated ex vivo, and mice treated with FLASH showed higher response rates and longer survival time than mice treated with CONV in an in vivo tumor model.

Conclusions: Collectively, these results suggest that FLASH spares mitochondrial function in nontumorigenic cells, but not in PDAC cells, relative to CONV. The preservation of mitochondrial integrity in nontumorigenic cells may be a key mechanism underlying the reduced normal tissue toxicity observed with FLASH RT.

Keywords

FLASH radiation, mitochondria, pancreatic cancer, metabolism, radiation

Comments

Updated version available: A peer-reviewed version of this article, "Mitochondrial Responses to Conventional and Ultra-high Dose Rate (FLASH) Radiation.", has been published in Int J Radiat Oncol Biol Phys.

Published Open-Access

yes

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