ATP5F1B encodes the catalytic β-subunit of mitochondrial ATP synthase (Complex V), the final enzyme complex of oxidative phosphorylation 1. As part of the F₁F₀ ATP synthase, ATP5F1B forms the catalytic core together with ATP5F1A, coupling proton gradient-driven rotational mechanics of the central stalk to ATP synthesis from ADP 1. The complex consists of a soluble F₁ head domain (catalytic core) and a membrane-bound F₀ domain, linked by a rotating central stalk and stationary peripheral stalk 1. Dysfunction of ATP5F1B causes autosomal dominant mitochondrial uncoupling syndrome. A heterozygous de novo ATP5F1B variant identified in identical twins with congenital hypermetabolism resulted in loosened coupling between the proton motive force and ATP synthesis, causing elevated oxygen consumption, decreased mitochondrial membrane potential, and excessive energy expenditure 2. This disease mechanism reflects impaired energy efficiency rather than total energy production loss. ATP5F1B maintains critical importance in multiple pathological contexts. The protein stabilizes mitochondrial ATP synthase activity to protect against mitochondrial vulnerability in cancer progression 3 and interacts with Cend1 to enhance ATP synthesis during ischemic stroke injury 4. Additionally, ATP5F1B serves as a hub gene implicated in Alzheimer's disease pathophysiology through oxidative phosphorylation pathway dysfunction 5. Beyond mitochondrial localization, ATP5F1B appears on extracellular vesicle surfaces 6, suggesting potential extramitochondrial signaling roles requiring further investigation.