Protein disulfide-isomerase A4–NADH:ubiquinone oxidoreductase core subunit S3 protein–protein interface (PDIA4–NDUFS3 interface)

The Protein disulfide-isomerase A4 (PDIA4)–NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3) protein–protein interface is a critical regulatory junction that links endoplasmic reticulum (ER) stress to mitochondrial dysfunction (Kuo et al., 2020, Nature Communications). PDIA4 is an ER-resident chaperone that is significantly upregulated under metabolic stress, such as chronic hyperglycemia or obesity (UniProt P13667). In these pathological states, PDIA4 interacts with NDUFS3, a key subunit of mitochondrial Complex I, leading to its inhibition and subsequent degradation (Kuo et al., 2020). This interaction results in impaired mitochondrial respiration and excessive production of reactive oxygen species (ROS), which drives pancreatic beta-cell failure and contributes to the pathogenesis of type 2 diabetes (PubMed 32415110). Furthermore, this interface has been implicated in cancer cell survival, where PDIA4 helps modulate the redox environment to resist apoptosis (UniProt O75489). Small molecule inhibitors like CCF642 have been developed to target PDIA4, effectively disrupting this interaction and restoring mitochondrial function in preclinical models (PubChem CID 118705455). Consequently, the PDIA4–NDUFS3 interface is an emerging target for treating metabolic disorders and potentially certain types of cancer.

Other names

PDIA4-NDUFS3 interactionERP72-NDUFS3 interactionProtein disulfide-isomerase A4 and NADH:ubiquinone oxidoreductase core subunit S3 complex

Disruption of the PDIA4-NDUFS3 interaction to restore mitochondrial Complex I activity and reduce reactive oxygen species-mediated cellular damage.