Overview of mitochondrial cuproenzymes and copper chaperones. (A) Electron transport chain (complexes I–IV and ATP synthase) in the inner membrane of mitochondria. The complex IV renowned as cytochrome c oxidase (CcO) can reduce O₂ into H₂O, pumping proton from the matrix to the intermembrane space (IMS) to establish an electrochemical gradient for ATP synthesis. Mitochondrial SOD1 could detoxify superoxide anion (O₂^•−). Metallochaperones including Cox17, Sco1/2, Cox17, Cox11, and CCS mediate copper insertion into the cuproenzymes. (B) Coordination sphere of Cu_A site, heme a, and heme a₃/Cu_B in CcO (PDB 5Z62). (C) Coordination sphere of Cox11 (PDB 1SO9).

Regulation of CMGC kinases by prolyl hydroxylation. The activation of DYRK1s, a group of CMGC kinases, critically relies on the autophosphorylation of a tyrosine residue within the activation loop of the catalytic domain. This essential autophosphorylation event takes place during the kinase’s folding process and is facilitated by a unique folding intermediate. Notably, this folding intermediate differs from the mature conformation that results from prolyl hydroxylation by PHDs.