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Intestinal Epithelial Regeneration in Response to Ionizing Irradiation
Published on: July 27, 2022
Oxidative lipidomics of gamma-irradiation-induced intestinal injury
Yulia Y Tyurina1, Vladimir A Tyurin, Michael W Epperly
1Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Abstract:
Although gamma-irradiation-induced tissue injury has been associated with lipid peroxidation, the individual phospholipid molecular targets have not been identified. We employed oxidative lipidomics to qualitatively and quantitatively characterize phospholipid peroxidation in a radiosensitive tissue, the small intestine, of mice exposed to total body irradiation (TBI) (10 and 15 Gy). Using electrospray ionization mass spectrometry we found that the major classes of intestine phospholipids-phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol-included clusters with highly oxidizable molecular species containing docosahexaenoic fatty acid. Molecular species of cardiolipin were represented by only two major less oxidizable individual molecular species-tetralinoleoylcardiolipin and trilinoleoyl-mono-oleoylcardiolipin. Selective and robust oxidation of two anionic phospholipids-cardiolipin in mitochondria and phosphatidylserine outside of mitochondria-was observed 24 h after gamma-irradiation. MS analysis detected several TBI-induced molecular species of oxidized cardiolipin: (C(18:2))(3)(C(18:2)-OOH), (C(18:2))(2)(C(18:2)-OOH)(2), (C(18:2))(1)(C(18:2)-OOH)(3), and (C(18:2)-OOH)(4). The major molecular species involved in TBI-triggered peroxidation of phosphatidylserine included C(18:0)/C(22:6)-OOH, C(18:0)/C(22:5)-OOH, and C(18:0)/C(22:4)-OOH. More abundant phospholipids-phosphatidylcholine and phosphatidylethanolamine-did not reveal any oxidative stress responses despite the presence of highly oxidizable docosahexaenoic fatty acid residues in their molecular species. A marked activation of caspases 3/7 that was detected in the intestine of gamma-irradiated mice indicates the involvement of apoptotic cell death in the TBI injury. Given that oxidized molecular species of cardiolipin and phosphatidylserine accumulate during apoptosis of different cells in vitro we speculate that cardiolipin and phosphatidylserine oxidation products may be useful as potential biomarkers of gamma-irradiation-induced intestinal apoptosis in vivo and may represent a promising target for the discovery of new radioprotectors and radiosensitizers.
Insights
Gamma irradiation causes lipid peroxidation in the small intestine, specifically targeting cardiolipin and phosphatidylserine. These oxidized phospholipids may serve as biomarkers for radiation-induced apoptosis and potential targets for radioprotectors.
Area of Science:
- Biochemistry
- Molecular Biology
- Radiation Biology
Background:
- Gamma irradiation induces tissue injury linked to lipid peroxidation.
- Specific phospholipid molecular targets of this injury remain unidentified.
Purpose of the Study:
- To characterize phospholipid peroxidation in the radiosensitive mouse small intestine following total body irradiation (TBI).
- To identify specific oxidized phospholipid molecular species and their cellular localization.
- To explore the potential of these oxidized phospholipids as biomarkers and therapeutic targets.
Main Methods:
- Oxidative lipidomics using electrospray ionization mass spectrometry (ESI-MS).
- Analysis of phospholipids in mouse small intestine after 10 and 15 Gy TBI.
- Assessment of caspase-3/7 activation as an indicator of apoptosis.
Main Results:
- Selective oxidation of cardiolipin (CL) in mitochondria and phosphatidylserine (PS) outside mitochondria was observed 24 hours post-TBI.
- Specific oxidized molecular species of CL and PS were identified, including those with docosahexaenoic acid (DHA) residues.
- Abundant phospholipids like phosphatidylcholine (PC) and phosphatidylethanolamine (PE) showed no oxidative response.
- TBI induced marked activation of caspases 3/7, indicating apoptotic cell death.
Conclusions:
- Oxidized cardiolipin and phosphatidylserine species are key molecular targets of gamma-irradiation-induced intestinal injury.
- These oxidized phospholipids may serve as sensitive biomarkers for gamma-irradiation-induced apoptosis in vivo.
- Targeting CL and PS oxidation presents a promising strategy for developing radioprotectors and radiosensitizers.
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