ISCA2 (iron-sulfur cluster assembly 2) is a mitochondrial protein essential for the late-stage maturation of [4Fe-4S] cluster-containing proteins. ISCA2 functions as part of a coordinated assembly complex with ISCA1 and NFU1, where ISCA1 orchestrates interactions between ISCA2 and NFU1 to facilitate safe cluster transfer to target apo-proteins 1. Structurally, ISCA2 binds [2Fe-2S] or [4Fe-4S] clusters in a dimeric state and receives [2Fe-2S] clusters from GRX5, which are assembled into [4Fe-4S] clusters within the ISCA1/ISCA2 heterodimer 2. ISCA2 also recruits IBA57 to form a stable [2Fe-2S] cluster-mediated complex resistant to oxidative stress 3. Depletion of ISCA2 causes severe mitochondrial dysfunction, including cristae disruption and diminished activity of [4Fe-4S] proteins such as aconitase and respiratory complex I 4. Pathologically, ISCA2 mutations cause multiple mitochondrial dysfunctions syndrome 4, presenting as neonatal leukoencephalopathy with elevated lactate and progressive neurodegeneration 5. Additionally, ISCA2 expression impacts HIF-1/2α translation and ferroptosis sensitivity in renal carcinoma, suggesting potential therapeutic targets 6.