Iron-sulfur cluster assembly 2 homolog (ISCA2)

Iron-sulfur cluster assembly 2 homolog (ISCA2) is a mitochondrial protein that plays a critical role in the late-stage biogenesis of [4Fe-4S] clusters, which are essential cofactors for various metabolic enzymes [1, 4]. It functions as part of the mitochondrial iron-sulfur cluster (ISC) assembly machinery, specifically facilitating the maturation of [4Fe-4S] proteins like those found in respiratory chain complexes I and II and the citric acid cycle enzyme aconitase [1, 2]. Deficiencies in ISCA2 lead to Multiple Mitochondrial Dysfunctions Syndrome 4 (MMDS4), a devastating neurodegenerative condition characterized by early-onset leukoencephalopathy, developmental regression, and systemic metabolic failure [2, 3]. Currently, there are no approved small-molecule drugs that directly target ISCA2, but it remains a primary candidate for gene replacement therapies and metabolic bypass strategies aimed at restoring mitochondrial capacity [3, 4]. Because ISCA2 is vital for mitochondrial respiration and iron homeostasis, it serves as a key biomarker for diagnosing specific mitochondrial leukodystrophies [2, 4]. Its essential nature means that therapeutic approaches must focus on restoring rather than inhibiting its function to avoid severe cellular toxicity [1, 3]. Sources: UniProt (Q86U28) [1], OMIM (615317) [2], PubMed (PMID: 25326637) [3], PubMed (PMID: 28430804) [4].

Other names

HESB-like domain-containing protein 2HESBAMultiple mitochondrial dysfunctions syndrome 4 proteinMMDS4ISA2

There are currently no approved drugs that target ISCA2; however, therapeutic strategies under investigation focus on gene replacement therapy to restore functional protein levels in patients with loss-of-function mutations [2, 3].