CHCHD4 (MIA40) is a central oxidoreductase component of the mitochondrial disulfide relay system in the intermembrane space. It functions as a chaperone that catalyzes disulfide bond formation in substrate proteins including COX17, COX19, MICU1, and COA7, enabling their import and folding in the intermembrane space. The protein operates via a redox-dependent mechanism: reduced precursor proteins are translocated into mitochondria and form transient disulfide bridges with oxidized CHCHD4, allowing the substrates to fold stably within the intermembrane space; CHCHD4 is subsequently reoxidized by GFER/ERV1. This pathway is essential for respiratory chain complex assembly and biogenesis. CHCHD4 also regulates mitochondrial calcium uptake by promoting MICU1–MICU2 heterodimer formation. Beyond baseline respiration, CHCHD4 plays a critical role in hypoxia signaling; increased CHCHD4 expression enhances HIF-1α stabilization under hypoxic conditions and correlates with tumor grade and reduced patient survival in human cancers 1. Recent work shows CHCHD4 is regulated by NADH-activated AIF, which directly stimulates its chaperone activity and links cellular energy metabolism to mitochondrial protein import 2. CHCHD4 is essential for tumor cell growth 3, and its depletion impairs complex I assembly in C9orf72-linked amyotrophic lateral sclerosis patient-derived neurons 4, implicating the disulfide relay system in neurodegeneration.