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Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2)
- Target
- ISCA2
- Molecular classification
- Iron-sulfur cluster assembly factor, Mitochondrial protein, Other
01
Overview
Iron-sulfur cluster assembly 2 homolog, mitochondrial (ISCA2), is a mitochondrial matrix protein crucial for the biogenesis of [4Fe-4S] iron-sulfur clusters, which are essential cofactors for enzymes involved in mitochondrial respiration and metabolism. ISCA2 acts together with ISCA1 and IBA57 in the late steps of mitochondrial iron-sulfur cluster assembly. Loss or inhibition of ISCA2 disrupts mitochondrial function, impairs respiratory chain complexes, and can induce cell death, making it both a key factor in mitochondrial disease pathogenesis and a potential pharmacological target, especially in cancer research where its inhibition promotes ferroptosis.
- Other names
- ISCA2HBLD1ISA2HESB-like domain-containing protein 1MMDS4c14_5557
02
Mechanism of action
Inhibition of ISCA2 disrupts late-stage [4Fe-4S] cluster assembly, leading to defective mitochondrial function, decreased HIF-1α and HIF-2α protein levels, induction of iron starvation response, and ferroptosis in cancer cells
03
Biological functions
Mitochondrial [4Fe-4S] cluster biogenesisIron-sulfur cluster maturationSupport of mitochondrial respiratory chain complexes I and IIMaintenance of mitochondrial morphology and functionRegulation of HIF-1α and HIF-2α protein levels
04
Disease associations
Mitochondrial disorders (Multiple mitochondrial dysfunctions syndrome 4, MMDS4)Cancer (particularly clear cell renal cell carcinoma, via ferroptosis induction)Other (cellular iron homeostasis disorders)
05
Safety considerations
Disruption of ISCA2 function causes severe mitochondrial dysfunction, defects in respiratory chain complex assembly, loss of mitochondrial cristae, and cell deathKnockdown or inhibition can impair essential energy metabolism in non-cancerous cells
06
Interacting drugs
Experimental small molecule ISCA2 inhibitors, including compounds identified as #1 and #25 in research studies
07
Biomarkers
ISCA2 expression levels for mitochondrial disease diagnosisDecreased HIF-1α and HIF-2α protein levels as response biomarkers (in cancer research)Lipoylation status of mitochondrial [4Fe-4S] dependent enzymes (DLAT, DLST) as readouts of ISCA2 activity
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