Novel penetrating cations for targeting mitochondria

Area of Science:

• Mitochondrial biology
• Medicinal chemistry
• Biochemistry

Background:

• Mitochondria are key targets for therapeutic interventions due to their role in cellular energy production and oxidative stress.
• Developing effective mitochondria-targeted compounds requires strategies to overcome membrane barriers and ensure accumulation within mitochondria.
• Antioxidants are crucial for combating oxidative damage implicated in aging and various diseases.

Purpose of the Study:

• To design and synthesize novel mitochondria-targeted compounds by conjugating penetrating cations with plastoquinone, an antioxidant.
• To evaluate the efficacy of these conjugates in preventing lipid peroxidation and protecting cells against oxidative stress-induced damage.
• To investigate the mechanism of action, including proton transport and antioxidant activity, of these novel compounds.

Main Methods:

• Synthesis of novel cationic conjugates linking rhodamine, berberine, or palmatine with plastoquinone or its analogs.
• Testing in model lipid membranes, isolated mitochondria, and cultured human fibroblasts.
• Assays for lipid peroxidation inhibition, mitochondrial protection against hydrogen peroxide-induced apoptosis, and proton transport.

Main Results:

• Conjugates (SkQR1, SkQBerb, SkQPalm) penetrated lipid membranes and accumulated in mitochondria.
• Reduced forms of SkQR1, SkQBerb, and SkQPalm inhibited lipid peroxidation at nanomolar concentrations.
• SkQR1, SkQBerb, and SkQPalm protected human fibroblasts from hydrogen peroxide-induced mitochondrial fragmentation and apoptosis, with SkQR1 being highly potent.

Conclusions:

• Novel mitochondria-targeted cationic conjugates, particularly rhodamine-based ones, exhibit potent antioxidant and cytoprotective effects.
• These compounds act as selective mild uncouplers and antioxidants, offering dual mechanisms for cellular protection.
• The developed compounds are promising candidates for therapeutic applications against pathologies and aging associated with mitochondrial dysfunction and oxidative stress.