ATP5PB

ATP5PB (subunit b) is a component of the F0 sector of the mitochondrial ATP synthase, where it forms part of the peripheral stalk and directly contacts cardiolipin in the inner mitochondrial membrane (PMID:23872101). In cardiac interfibrillar mitochondria this subunit b–cardiolipin interaction is lost in type 1 diabetes, coinciding with diminished ATP synthase activity, linking the lipid contact to enzyme function (PMID:23872101). Genetic deletion of the membrane domain of subunit b in human cells preserves the calcium-triggered, cyclosporin A–sensitive permeability transition pore, establishing that this domain is dispensable for permeability transition pore formation (PMID:28784775). Subunit b is susceptible to covalent modification at cysteine residues by reactive electrophiles such as 6PPD-quinone, and this adduction tracks with reduced respiratory chain Complex I and IV activities, lowered ATP content and membrane potential, and elevated mitochondrial ROS (PMID:41714849). Beyond these observations, the structural and regulatory mechanisms of ATP5PB have not been further characterized in the available corpus.

1. 2013 Medium

   Established that subunit b makes a direct, functionally relevant contact with cardiolipin in the inner membrane and that loss of this contact accompanies reduced ATP synthase activity in disease.

   Evidence Co-immunoprecipitation/direct interaction assay between cardiolipin and ATP synthase subunits in isolated cardiac mitochondrial subpopulations, with enzymatic activity readout in type 1 diabetic mitochondria

   PMID:23872101

   Open questions at the time

   • Single lab, correlational link between lost cardiolipin binding and reduced activity
   • Does not define the residues or structural interface mediating cardiolipin binding
   • Mechanism connecting cardiolipin loss to activity decline not resolved
2. 2017 High

   Resolved whether the subunit b membrane domain contributes to the permeability transition pore by showing the pore's defining properties persist without it.

   Evidence CRISPR disruption generating clonal HAP1-Δb cells with calcium-triggered swelling and cyclosporin A sensitivity assays

   PMID:28784775

   Open questions at the time

   • Does not address whether other ATP synthase subunits contribute to the pore
   • Effect of the deletion on ATP synthesis itself not the focus
   • Does not define the molecular identity of the pore
3. 2026 Medium

   Identified subunit b cysteines as covalent targets of reactive electrophiles, linking chemical adduction to broad mitochondrial dysfunction.

   Evidence Sulfhydryl-reactive proteomics identifying 6PPD-quinone covalent targets with respiratory complex activity, ATP, membrane potential, and ROS assays in A549 cells

   PMID:41714849

   Open questions at the time

   • Single lab, single study with correlational functional readouts
   • Does not establish that ATP5PB adduction is causal for the Complex I/IV deficits
   • Specific modified cysteine residues and downstream mechanism not mapped

• How cardiolipin binding, cysteine modification, and peripheral stalk function mechanistically integrate to regulate ATP synthase activity remains unresolved.
• No structural model of the subunit b cardiolipin interface
• Causal chain from cysteine adduction to enzyme inhibition undefined
• Role of subunit b in ATP synthase assembly/dimerization not characterized in the corpus