Journal article
Mitochondrial Ca 2+ Uptake Drives Endothelial Injury By Radiation Therapy
Arteriosclerosis, thrombosis, and vascular biology, Vol.42(9), pp.1121-1136
09/2022
DOI: 10.1161/ATVBAHA.122.317869
PMCID: PMC9394506
PMID: 35899616
Abstract
Background:
Radiation therapy strongly increases the risk of atherosclerotic vascular disease, such as carotid stenosis. Radiation induces DNA damage, in particular in mitochondria, but the upstream and downstream signaling events are poorly understood. The objective of this study was to define such mechanisms.
Methods:
Endothelial-specific MCU (mitochondrial Ca
2+
uniporter) knockout and C57Bl6/J mice with or without a preinfusion of a mitoTEMPO (mitochondrial reactive oxygen species [ROS] scavenger) were exposed to a single dose of cranial irradiation. 24, and 240 hours postirradiation, vascular reactivity, endothelial function, and mitochondrial integrity were assessed ex vivo and in vitro.
Results:
In cultured human endothelial cells, irradiation with 4 Gy increased cytosolic Ca
2+
transients and the mitochondrial Ca
2+
concentration ([Ca
2+
]
mt
) and activated MCU. These outcomes correlated with increases in mitochondrial ROS (
mt
ROS), loss of NO production, and sustained damage to mitochondrial but not nuclear DNA. Moreover, irradiation impaired activity of the ETC (electron transport chain) and the transcription of ETC subunits encoded by mitochondrial DNA (
mt
DNA). Knockdown or pharmacological inhibition of MCU blocked irradiation-induced
mt
ROS production,
mt
DNA damage, loss of NO production, and impairment of ETC activity. Similarly, the pretreatment with mitoTEMPO, a scavenger of
mt
ROS, reduced irradiation-induced Ca
2+
entry, and preserved both the integrity of the
mt
DNA and the production of NO, suggesting a feed-forward loop involving [Ca
2+
]
m
and
mt
ROS. Enhancement of DNA repair in mitochondria, but not in the nucleus, was sufficient to block prolonged
mt
ROS elevations and maintain NO production. Consistent with the findings from cultured cells, in C57BL/6J mice, head and neck irradiation decreased endothelium-dependent vasodilation, and
mt
DNA integrity in the carotid artery after irradiation. These effects were prevented by endothelial knockout of MCU or infusion with mitoTEMPO.
Conclusions:
Irradiation-induced damage to
mt
DNA is driven by MCU-dependent Ca
2+
influx and the generation of
mt
ROS. Such damage leads to reduced transcription of mitochondrial genes and activity of the ETC, promoting sustained
mt
ROS production that induces endothelial dysfunction. Our findings suggest that targeting MCU and
mt
ROS might be sufficient to mitigate irradiation-induced vascular disease.
Details
- Title: Subtitle
- Mitochondrial Ca 2+ Uptake Drives Endothelial Injury By Radiation Therapy
- Creators
- Karima Ait-Aissa - Roy J. and Lucille A. Carver College of MedicineOlha M. Koval - University of IowaNathanial R. Lindsey - University of IowaIsabella M. Grumbach - Iowa City VA Health Care System
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.42(9), pp.1121-1136
- DOI
- 10.1161/ATVBAHA.122.317869
- PMID
- 35899616
- PMCID
- PMC9394506
- NLM abbreviation
- Arterioscler Thromb Vasc Biol
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 09/2022
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984359590702771
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