H₂S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Cellular Biology

Background:

• Hydrogen sulfide (H2S) is an emerging gasotransmitter with demonstrated cardioprotective effects.
• Iron is essential for numerous cellular processes, including mitochondrial function.
• Dysregulation of iron metabolism is implicated in cellular damage and disease.

Purpose of the Study:

• To investigate the regulatory role of H2S in iron metabolism and mitochondrial function in rat cardiac cells.
• To elucidate the protective mechanisms of H2S against rotenone-induced ischemic cell damage.

Main Methods:

• Cultured rat cardiac cells were treated with rotenone to induce an in vitro model of ischemic damage.
• Hydrogen sulfide (H2S) supplementation and deferiprone (an iron chelator) were used to assess protective effects.
• Mitochondrial function, oxidative stress, lipid peroxidation, GPx4 expression, intracellular iron levels, and iron transport proteins were analyzed.

Main Results:

• Rotenone induced oxidative stress, lipid peroxidation, decreased mitochondrial membrane potential, and ATP generation, leading to cell death.
• H2S supplementation protected against rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage.
• H2S maintained GPx4 expression, regulated intracellular iron levels, inhibited mitochondrial iron efflux (ABCB8), and promoted Fe-S cluster biogenesis (NFS1).
• Rotenone stimulated iron-dependent H2S generation.

Conclusions:

• H2S protects cardiac cells from ischemic damage by preserving mitochondrial function and maintaining intracellular iron homeostasis.
• H2S modulates mitochondrial iron transport and Fe-S cluster biogenesis, contributing to its cardioprotective effects.
• Targeting H2S pathways may offer therapeutic strategies for cardiovascular diseases involving ischemic injury.