# Leveraging mitochondrial function to combat radiation therapy-induced microvascular disease

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Approximately 200,000 veterans receive cancer treatment at Veterans Health Administration facilities. With
improving survival rates for many cancers, the deleterious long-term cardiovascular side effects of cancer
therapies have become increasingly apparent. For many of the cancers that frequently occur among veterans,
radiation therapy (RT) is an integral component of treatment. Despite improvements in the techniques used to
target RT to the cancer tissue, some radiation always reaches surrounding normal tissue. Endothelial damage
within the small blood vessels or “radiation endotheliopathy” has been postulated as a major cause of RT-
induced injury of normal tissue. Many post-radiation syndromes have been attributed to radiation
endotheliopathy. One of them is cognitive decline, which is estimated to affect as many as 90% of patients
after brain RT. Mechanistically, radiation endotheliopathy is believed to be initiated by mitochondrial injury,
leading to chronic oxidative stress and endothelial dysfunction over a period of years. Thus, intervention at the
time of RT is likely critical for reducing radiation endotheliopathy and its sequelae, including cognitive decline.
The discovery of effective mitigators will require a unified view of the pathways by which RT-related
mitochondrial injury influences various steps in this progression; this has not been achieved to date.
 The objective of the proposed project is to identify the mechanisms by which mitochondrial injury promotes
radiation endotheliopathy, and to test whether protection from mitochondrial injury prevents adverse short- and
long-term effects of RT in small blood vessels. RT induces mitochondrial DNA damage, perturbs ATP
production, enhances the mitochondrial membrane potential, Ca2+ uptake and reactive oxygen species (ROS)
production. The mitochondrial Ca2+ uniporter (MCU) regulates Ca2+ uptake into the mitochondrial matrix and
was recently reported as being redox-dependent. Mitochondrial Ca2+ augments ROS production that promotes
further mitochondrial dysfunction. Thus, we posit that MCU in endothelial cells (ECs) drives a feed-forward
circuit with mitochondrial ROS that leads to long-term adverse effects of RT, including cognitive decline after
brain RT. Indeed, published data from our laboratory demonstrate that blocking mitochondrial Ca2+ uptake is
sufficient to reduce mitochondrial ROS production and protect EC barrier function. Thus, our central
hypothesis is that MCU-mediated Ca2+ uptake by mitochondria is required for excessive ROS
production after RT, and thus for chronic mitochondrial DNA damage, blood brain barrier (BBB)
breakdown, capillary loss, and cognitive decline. This hypothesis is further supported by our strong pilot
data that inhibition of MCU in ECs during RT abolishes mitochondrial DNA damage in vitro and protects
against BBB breakdown in vivo. Our novel tools and assays put us in the perfect position to perform the
proposed study. These include genetic models...

## Key facts

- **NIH application ID:** 10447052
- **Project number:** 5I01BX000163-13
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Isabella Maria Grumbach
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2010-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447052

## Citation

> US National Institutes of Health, RePORTER application 10447052, Leveraging mitochondrial function to combat radiation therapy-induced microvascular disease (5I01BX000163-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10447052. Licensed CC0.

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