Amyloid-β-Dependent Inactivation of the Mitochondrial Electron Transport Chain at Low Transmembrane Potential: An...

Cerebral hypoperfusion-induced hypoxia, a condition that impairs oxygen utilization and thus ATP production by mitochondrial oxidative phosphorylation (oxphos), is thought to contribute to neural degeneration in Alzheimer's disease. However, hypoxia upregulates the generation of amyloid-β (Aβ), a group of peptides known to impair/inhibit the electron transport chain (ETC) of reactions that support oxphos in the inner mitochondrial membrane (IMM). This is a hypothesis paper that reconciles the hypoxia-induced upregulation of Aβ with Aβ's ETC-inhibiting action and, specifically, posits an oxphos-enhancing effect of this inhibition under conditions of newly developing or otherwise mild hypoxia. This effect is typically transient; that is, under conditions of prolonged or severe hypoxia, the oxphos-enhancing activity is overwhelmed by Aβ's well-known toxic actions on mitochondria and other cellular components. The hypothesis is motivated by evidence that the IMM transmembrane potential Ψm, an important determinant of ETC activity, exhibits heterogeneity, i.e., a range of values, among a given local population of mitochondria. It specifically proposes that during oxygen limitation, Aβ selectively inactivates ETC complexes in mitochondria that exhibit relatively low absolute values of Ψm, thereby suppressing oxygen binding and consumption by complex IV of the ETC in these mitochondria. This effect of Aβ on low-Ψm mitochondria is hypothesized to spare hypoxia-limited oxygen for oxphos-enabling utilization by the ETC of the remaining active, higher-Ψm local mitochondria, and thereby to increase overall ATP generated collectively by the local mitochondrial population, i.e., to ameliorate hypoxia-induced oxphos reduction. The protective action of Aβ hypothesized here may slow the early development of hypoxia-associated cellular deterioration/loss in Alzheimer's disease and perhaps other neurodegenerative diseases.