Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis
Francesca Alves, Darius J.R. Lane, Adam Wahida, Md. Jakaria, Paweł Kalinowski, Adam Southon, Abdel Ali Belaidi, Teresa Samperi‐Esteve, Triet Phu Minh Nguyen, Lei Peng, Marcus Krueger, Stefan Mueller, Marcus Conrad, Puja Agarwal, Sue E. Leurgans, Julie Schneider, Ashley I. Bush, Scott Ayton
Abstract
Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.