Mortalin and PINK1/Parkin-Mediated Mitophagy Represent Ovarian Cancer-Selective Targets for Drug Development

Area of Science:

• Mitochondrial biology
• Cancer cell biology
• Drug discovery

Background:

• Mortalin is a mitochondrial chaperone crucial for protein import, often overexpressed in ovarian cancer, correlating with poor prognosis.
• The investigational drug SHetA2 interacts with mortalin, potentially releasing its client proteins and affecting cellular processes.

Purpose of the Study:

• To investigate the molecular interactions between SHetA2 and mortalin.
• To elucidate the distinct cellular and molecular responses of ovarian cancer versus noncancerous cells to SHetA2 treatment.
• To evaluate the therapeutic potential of SHetA2 in ovarian cancer models.

Main Methods:

• Surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) to study SHetA2-mortalin interactions.
• Cellular assays to assess mitochondrial function, calcium levels, autophagy, and mitophagy.
• In vivo studies using ovarian cancer xenografts.

Main Results:

• SHetA2 binds directly to mortalin's substrate-binding domain at low micromolar concentrations, selectively killing cancer cells.
• SHetA2 disrupts mortalin import, mortalin/inositol 1,4,5-trisphosphate receptor complexes, and oxidative phosphorylation in both cell types.
• Distinct effects observed in cancer cells include reduced calcium, altered mitochondrial dynamics, and induced mitophagy, while noncancerous cells show increased mitochondrial branching and resistant autophagy.
• SHetA2 inhibits tumor growth and improves survival in ovarian cancer xenografts.

Conclusions:

• SHetA2 directly binds mortalin's SBD, leading to differential cellular responses in ovarian cancer and noncancerous cells.
• SHetA2 demonstrates selective cytotoxicity towards ovarian cancer cells, primarily through the induction of mitophagy.
• SHetA2 shows promise as a therapeutic agent for ovarian cancer, warranting further clinical investigation.