Mitochondrial dysfunction induced by different concentrations of gadolinium ion
Jie Zhao1, Zhi-Qiang Zhou1, Jian-Cheng Jin1
1State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China.
Chemosphere
|December 11, 2013
Summary
Gadolinium (Gd(3+)) toxicity in mitochondria, a key factor in MRI contrast agent safety, is linked to mitochondrial permeability transition pore opening. This study elucidates Gd(3+) interactions with mitochondria, informing safer contrast agent development.
Area of Science:
- Biochemistry
- Cell Biology
- Medical Imaging
Background:
- Gadolinium-based compounds are widely used as paramagnetic contrast agents in MRI.
- The gadolinium ion (Gd(3+)) may induce cell apoptosis through mitochondrial effects.
- The precise mechanism of Gd(3+) interaction with mitochondria remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which Gd(3+) interacts with mitochondria.
- To identify key factors involved in Gd(3+)-induced mitochondrial dysfunction.
- To provide insights for the safe application of Gd-based MRI contrast agents.
Main Methods:
- Assessment of mitochondrial swelling, transmembrane potential, and membrane fluidity.
- Induction of mitochondrial permeability transition pore (mtPTP) opening with Gd(3+) and protection with Cyclosporin A (CsA).
- Transmission electron microscopy (TEM) for observing mitochondrial changes and Cytochrome c (Cyt c) release.
- Evaluation of thiol (-SH) group protection using monobromobimane (+) (MBM(+)) and dithiothreitol (DTT).
- Analysis of Gd(3+) effects on mitochondrial membrane lipid peroxidation.
Main Results:
- Gd(3+) induces mitochondrial swelling, collapses transmembrane potential, and decreases membrane fluidity, leading to mtPTP opening.
- High concentrations of Gd(3+) (500 μM) trigger mtPTP opening, confirmed by CsA's protective effect.
- TEM revealed mitochondrial outer membrane breakdown and volume expansion, accompanied by Cyt c release.
- MBM(+) and DTT protected thiol groups, suggesting Gd(3+) toxicity may involve chelation of -SH groups on membrane proteins.
- Gd(3+) inhibits mitochondrial lipid peroxidation, indicating potential interaction with anionic lipids.
Conclusions:
- Gd(3+)-induced mtPTP opening is a critical mechanism underlying its mitochondrial toxicity.
- The toxicity of Gd(3+) may stem from its chelation of thiol groups on membrane proteins and interaction with anionic lipids.
- Understanding these interactions is crucial for enhancing the safety profile of gadolinium-based MRI contrast agents.
