International journal of radiation oncology, biology, physics · 2026
Mitochondrial Responses to Conventional and Ultra-High Dose Rate (FLASH) Radiation.
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Caggiano Emily G, Elizondo Maryam E, Hernandez Alan Lopez, Waldrop Trey, Liu Kevin, Gatica-Gutierrez Henry, Vargas-Hernández Sofía, Mims Nefetiti, Acevedo-Diaz Ariana, Velasquez Brett, Neil Denae, Aguilar Edgardo, Meyer Matthew D, Echeverria Gloria V, Koong Albert C, Spiotto Michael T, Gustavsson Anna-Karin, Schüler Emil
Аннотация
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 radiation (CONV) RT. However, the mechanisms underlying the observed FLASH effect are unknown. We hypothesized that 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 AND MATERIALS: 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 similar levels of mitochondrial damage in response to CONV and FLASH, but nontumorigenic pancreatic cells were spared by FLASH. Ex vivo measurements recapitulated the in vitro findings, and in vivo, mice bearing subcutaneous LSL-KRASG12D; Trp53fl/+; Ptf1⍺ Cre (KPC) tumors had comparable tumor growth delay with FLASH and CONV, whereas longer survival after FLASH reflected reduced radiation-induced toxicity rather than greater tumor control.
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.
METHODS AND MATERIALS: 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 similar levels of mitochondrial damage in response to CONV and FLASH, but nontumorigenic pancreatic cells were spared by FLASH. Ex vivo measurements recapitulated the in vitro findings, and in vivo, mice bearing subcutaneous LSL-KRASG12D; Trp53fl/+; Ptf1⍺ Cre (KPC) tumors had comparable tumor growth delay with FLASH and CONV, whereas longer survival after FLASH reflected reduced radiation-induced toxicity rather than greater tumor control.
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.