GRPEL1 (GrpE like 1, mitochondrial) functions as an essential nucleotide exchange factor that regulates mitochondrial Hsp70 (mtHSP70/mortalin) chaperone activity. GRPEL1 facilitates ADP-ATP exchange at mtHSP70's nucleotide-binding domain, controlling the chaperone's binding to substrate proteins and modulating its function 1. Structural studies reveal that GRPEL1 exhibits remarkably higher affinity for ADP-bound mtHSP70 compared to GRPEL2, and can induce opening of the nucleotide binding cleft to facilitate ADP release 2. GRPEL1 works synergistically with mortalin to stabilize proteins, assemble protein complexes, and facilitate protein import into the mitochondrial matrix 3. The protein plays critical roles in mitochondrial protein quality control and is involved in Fe-S cluster biogenesis 1. GRPEL1 has significant disease relevance, being downregulated in osteoarthritis where it functions as a diagnostic biomarker 4. In glioblastoma, acetylation of mtHSP70 at specific lysine residues enhances its binding to GRPEL1, regulating the mitochondrial unfolded protein response and tumor progression 5. Additionally, GRPEL1-enriched exosomes can activate PINK1-mediated mitophagy, offering therapeutic potential for cartilage repair 6.