ATP5F1D encodes the delta subunit of mitochondrial ATP synthase (Complex V), a critical component of oxidative phosphorylation. The protein functions as a structural element of the F1 catalytic domain, where it assembles with the central stalk and contributes to the rotary mechanism coupling proton translocation across the inner mitochondrial membrane to ATP synthesis 1. ATP5F1D is essential for F1 assembly intermediate formation during ATP synthase biogenesis 2. Biallelic mutations in ATP5F1D cause mitochondrial complex V deficiency, presenting with episodic metabolic decompensation, metabolic acidosis, and hyperammonemia, accompanied by impaired F1F0 ATP synthase assembly and reduced complex V activity 3. In pathological contexts, ATP5F1D dysregulation drives disease progression: succinate accumulation downregulates ATP5F1D, triggering endothelial pyroptosis and mitochondrial dysfunction relevant to atherosclerosis 4. In endometrial cancer, ATP5F1D upregulation correlates with enhanced oxidative phosphorylation and paradoxically favorable prognosis, though knockdown suppresses cancer cell proliferation by inhibiting mitochondrial ROS-mediated pyroptosis 5. ATP5F1D serves as a diagnostic biomarker for high-grade endometrial cancer and immune infiltration status 6. In sporadic ALS, ATP5F1D downregulation suggests compromised metabolic resilience 7. These findings establish ATP5F1D as a pivotal regulator of mitochondrial energy metabolism with multifaceted roles in metabolic disease, cancer, and neurodegeneration.