ISCA1 (iron-sulfur cluster assembly 1) is a mitochondrial protein that orchestrates the late-stage maturation of [4Fe-4S] iron-sulfur clusters in mitochondrial proteins 1. ISCA1 functions as a central coordinator by binding both ISCA2 and NFU1, facilitating formation of a transient ternary complex that safely transfers [4Fe-4S] clusters from their assembly site to recipient apo proteins 1. This process is essential for activating critical mitochondrial enzymes including aconitase, respiratory complex I, and lipoic acid synthase; depletion of ISCA1 causes swollen mitochondria with diminished cristae membranes and reduced [4Fe-4S] enzyme activity 2. While primarily mitochondrial, ISCA1 also localizes to the cytosol where it interacts with IOP1/NARFL to support cytosolic iron-sulfur protein biogenesis 3. Clinically, ISCA1 mutations cause Multiple Mitochondrial Dysfunction Syndrome 5 (MMDS5), a rare disease characterized by neurological deterioration, seizures, and energy depletion 4. Neuron-specific Isca1 knockout rats developed developmental retardation, neuronal death, mitochondrial fragmentation, and reduced ATP production, providing a disease model extending the therapeutic window 4. Emerging evidence suggests ISCA1 expression correlates with cancer progression and immune checkpoint markers in various malignancies, particularly bladder and thyroid carcinomas, indicating potential prognostic utility 56.