The leishmanicidal activity of artemisinin is mediated by cleavage of the endoperoxide bridge and mitochondrial...

Area of Science:

• Parasitology
• Pharmacology
• Biochemistry

Background:

• Endoperoxides are known to kill malaria parasites by generating cytotoxic radicals.
• Leishmania parasites possess a compromised antioxidant defense and high iron content, making them potential targets for endoperoxide-based therapies.

Purpose of the Study:

• To elucidate the mechanism of artemisinin-induced apoptotic-like death in Leishmania promastigotes.
• To investigate the role of reactive oxygen species and mitochondrial dysfunction in artemisinin's antileishmanial activity.

Main Methods:

• Flow cytometry was used to confirm reactive oxygen species (ROS) formation.
• Mitochondrial function was assessed by measuring electron transport chain complex activity, membrane potential, and adenosine triphosphatase (ATP) levels.

Main Results:

• Artemisinin induced significant ROS formation in Leishmania promastigotes.
• Mitochondrial complexes I-III and II-III were inhibited, but mitochondrial superoxide generation and oxygen consumption remained largely unaffected, indicating minimal electron transport chain impairment.
• Artemisinin caused mitochondrial membrane depolarization and substantial ATP depletion without enhanced ATP hydrolysis.

Conclusions:

• Endoperoxide-mediated radical formation by artemisinin is the primary driver of its antileishmanial activity.
• Secondary mitochondrial dysfunction, including ATP depletion, contributes to the parasite's death.
• Endoperoxides represent a promising therapeutic strategy for leishmaniasis, warranting further pharmacological investigation.