IDH3A encodes the catalytic alpha subunit of isocitrate dehydrogenase 3 (NAD+), a mitochondrial enzyme catalyzing isocitrate decarboxylation to alpha-ketoglutarate in the tricarboxylic acid (TCA) cycle 1. IDH3A functions as part of a heterotetrameric complex with IDH3B and IDH3G subunits, with full enzymatic activity requiring cooperative assembly of both heterodimers [UniProt]. Beyond mitochondrial energy metabolism, IDH3A participates in a nonclassical nuclear TCA cycle regulating epigenetic chr15 dynamics and transcription 1. IDH3A expression in cardiac and skeletal muscle tissues is regulated by PGC-1α-dependent transcriptional mechanisms linking metabolic adaptation to exercise 2. Functionally, IDH3A maintains mitochondrial respiratory reserve capacity, particularly critical in the retina which operates with limited reserve 3. Mutations in IDH3A cause retinitis pigmentosa-90, a progressive retinal degeneration associated with reduced mitochondrial respiration and photoreceptor stress, while complete loss is embryonic lethal 34. Recent evidence identifies IDH3A as a therapeutic target: lysine crotonylation of IDH3A at K199 protects cardiomyocytes from ischemia-reperfusion injury-induced apoptosis 5, while direct inhibition of IDH3A by celastrol shows anticancer activity through metabolic reprogramming 6. IDH3A also emerges as a biomarker for atopic dermatitis severity linked to mitochondrial dysfunction 7.