biorxiv2026-08-04score 91
Cholesterol in APOE4 astrocytes truncates cristae, drops Complexes I and IV, and leaves cells dependent on a reversing ATP synthase
Lee, Holt and colleagues find that APOE4 mouse astrocytes with high intracellular cholesterol build sparse, truncated cristae and extra crista-junction complexes, lose respiratory Complexes I and IV, and respire less. Membrane potential still rises, because proton leak is low and ATP synthase runs in reverse, hydrolyzing ATP to support the gradient. Oligomycin becomes selectively toxic, and sequestering cholesterol with methyl-β-cyclodextrin removes that toxicity. The lost complexes imply iron-sulfur, heme, and copper sites. The abstract reports the complexes, not the metals. The enzyme they actually catch misbehaving is ATP synthase.
