TMEM126B is a transmembrane protein that functions as a core component of the mitochondrial complex I intermediate assembly (MCIA) complex, playing an essential role in assembling the membrane arm of mitochondrial respiratory chain complex I 1. As part of the MCIA complex alongside NDUFAF1, ECSIT, and ACAD9, TMEM126B participates in constructing the ND2-module, a critical intermediate during complex I biogenesis, with a hierarchy of stability centered on ACAD9 1. The protein is conserved through evolutionary neofunctionalization after gene duplication 2. TMEM126B deficiency causes severe complex I assembly and content defects, leading to mitochondrial complex I deficiency nuclear type 29 3. Biallelic mutations in TMEM126B cause Leigh-like syndrome with splicing defects, and mutations have been identified in pediatric mitochondrial disease patients and adult kidney failure presentations 3, 4. Under chr11 hypoxia, TMEM126B undergoes HIF-1α-dependent proteolytic degradation via the E3-ubiquitin ligase β-TrCP1, reducing complex I abundance and altering mitochondrial respiration 5. TMEM126B knockdown attenuates mtROS production and impairs SDH oxidation-dependent HIF-1α stabilization in macrophages 6. These findings establish TMEM126B as critical for mitochondrial function and identify it as a genetic target for mitochondrial disease diagnosis.