Kelch-like ECH-associated protein 1–Phosphoglycerate mutase family member 5 complex (Keap1–PGAM5 complex)

The Keap1–PGAM5 complex is a regulatory assembly formed by the interaction between Kelch-like ECH-associated protein 1 (Keap1) and the mitochondrial phosphatase Phosphoglycerate mutase family member 5 (PGAM5). Keap1 is primarily known as the substrate adapter for the Cullin 3-based E3 ubiquitin ligase that targets the antioxidant transcription factor Nrf2 for degradation. PGAM5, localized to the outer mitochondrial membrane, contains a conserved NXESGE motif that binds to the Kelch domain of Keap1, effectively anchoring Keap1 to the mitochondria and influencing its ability to regulate Nrf2. This complex serves as a critical link between mitochondrial status and the cellular oxidative stress response, playing significant roles in mitophagy and necroptosis. In disease contexts, the Keap1–PGAM5 axis is often dysregulated; for instance, in certain cancers, it can contribute to metabolic reprogramming and survival, while in neurodegenerative conditions like Parkinson's disease, it affects mitochondrial integrity. Therapeutic interest focuses on small molecules that can disrupt or stabilize this interaction to fine-tune cellular resilience against oxidative damage and mitochondrial dysfunction.

Other names

Keap1-PGAM5 interactionKeap1-PGAM5 axisKEAP1-PGAM5 protein complex

Inhibition of the protein-protein interaction between Keap1 and PGAM5 to prevent mitochondrial sequestration of Keap1, thereby modulating Nrf2-mediated antioxidant responses and mitochondrial quality control.