HIGD2A encodes a mitochondrial assembly factor that functions as a critical component in the biogenesis of cytochrome c oxidase (complex IV) and respiratory chain supercomplexes. As a structural subunit of complex IV, HIGD2A specifically controls assembly of the COX3 module and acts as a placeholder factor during the final maturation steps of complex IV, being replaced by NDUFA4 during respirasome assembly 1 2. HIGD2A's expression is dynamically regulated by hypoxia, glucose availability, and cell cycle progression through E2F1-mediated transcriptional control, enabling metabolic adaptation to environmental stress 3 4. Loss of HIGD2A leads to defective complex IV biogenesis, accumulation of assembly intermediates, reduced complex IV activity, and altered mitochondrial dynamics, including increased OPA1-mediated fusion and decreased FIS1-mediated fission 5 3. While HIGD2A is not directly implicated in cancer through mutations, its altered expression and DNA methylation patterns occur across multiple malignancies, particularly in Diffuse Large B-cell Lymphoma, suggesting involvement in cancer-associated metabolic reprogramming 6. HIGD2A also functions in skin barrier maintenance and asthma pathogenesis, with upregulation detected in allergic asthma 7. These findings establish HIGD2A as a multifunctional assembly factor essential for respiratory chain supercomplex biogenesis and cellular energetics.