SDHAF4 is a mitochondrial assembly factor essential for complex II (succinate dehydrogenase) assembly, a key enzyme linking the tricarboxylic acid cycle and electron transport chain 1. SDHAF4 binds to the flavoprotein SDHA in its FAD-bound form, facilitating assembly with the iron-sulfur protein SDHB into the SDH catalytic dimer while suppressing excess reactive oxygen species generation 1. Mechanistically, SDHAF4 mediates complex II assembly in the mitochondrial matrix, with tissue-specific expression patterns reflecting metabolic demands across organs 2. Clinically, SDHAF4 dysfunction has significant disease relevance. Cardiac-specific loss of Sdhaf4 suppresses complex II assembly, causing progressive dilated cardiomyopathy and lethal heart failure in mice through impaired mitochondrial dynamics and energy metabolism 3. Conversely, hepatic Sdhaf4 knockout improves systemic glucose tolerance and insulin sensitivity, suggesting context-dependent metabolic effects 4. In cancer, SDHAF4 translation is enhanced by METTL1-mediated tRNA modifications, promoting gastric cancer progression through complex II-dependent metabolic acceleration 5. Additionally, SDHAF4 mutations are identified in paragangliomas and pheochromocytomas 6, and SDHAF4 polymorphisms are associated with longevity in dogs 7, suggesting broader roles in age-related physiology.