HIGD1A is a mitochondrial inner membrane protein that functions as a critical regulator of cellular energy metabolism and stress responses. Primary Function: HIGD1A acts as a subunit of cytochrome c oxidase (Complex IV) and regulates respiratory complex and supercomplex biogenesis 1. Specifically, it supports Complex III biogenesis by facilitating UQCRFS1 incorporation and coordinates Complex IV assembly through interactions with COX subunits 1. Mechanism: Under hypoxic conditions, HIGD1A maintains mitochondrial integrity and enhances ATP generation by regulating cytochrome c oxidase activity, thereby promoting cell survival in mild-to-moderate hypoxia while inhibiting growth in severe hypoxia 2. Additionally, HIGD1A alleviates oxidative stress in granulosa cells via the NF-κB/SOD2 signaling pathway 3. Disease Relevance: HIGD1A translocates to the nucleus under DNA damage stress, where it promotes homologous recombination repair through RPA and 9-1-1 complex interactions 4. It also functions as a host restriction factor against hepatitis B virus by activating NF-κB signaling 5. Clinical Significance: HIGD1A represents a potential therapeutic target for hypoxia-related diseases, oxidative stress-induced infertility, cancer radio/chemo-resistance, and viral infections 2345.