Cytosolic cytochrome c represses ferroptosis

Area of Science:

• Cell Biology
• Biochemistry
• Molecular Oncology

Background:

• Cytochrome c (CYCS) release from mitochondria initiates caspase-dependent apoptosis.
• Ferroptosis is a distinct form of oxidative cell death characterized by lipid peroxidation and plasma membrane rupture.

Purpose of the Study:

• To investigate the novel role of cytosolic CYCS beyond its known function in apoptosis.
• To identify molecular mechanisms by which CYCS regulates ferroptosis.

Main Methods:

• Mass spectrometry and site-directed mutagenesis to identify protein complexes.
• Biochemical assays to measure enzyme activity and lipid peroxidation.
• In vitro cell culture and in vivo mouse tumor models to assess ferroptosis sensitivity.

Main Results:

• A novel cytosolic complex of CYCS and inositol polyphosphate-4-phosphatase type I A (INPP4A) was identified, distinct from the apoptotic apoptosome.
• The CYCS-INPP4A complex enhances INPP4A activity, increasing phosphatidylinositol-3-phosphate production.
• This complex prevents lipid peroxidation and ferroptotic cell death.
• The small molecule 10A3 disrupts the CYCS-INPP4A interaction, sensitizing cells and tumors to ferroptosis.

Conclusions:

• Cytosolic CYCS plays an inhibitory role in ferroptosis through interaction with INPP4A.
• The CYCS-INPP4A complex represents a new regulatory axis controlling cell death pathways.
• Targeting the CYCS-INPP4A interaction with compounds like 10A3 offers a potential strategy to induce ferroptosis in cancer therapy.