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bioRxiv · 10.64898/2026.06.25.734545

Mitochondrial Hsp60/10 Client Protein Decline Reveals Braak/Tau- and Cognition-Linked Proteostasis Vulnerabilities in Alzheimer's Disease

Sloane, A.·Kattunga, V. M.·Andersen, J. K.
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Abstract

BackgroundAlzheimers disease (AD) is classically defined by amyloid and tau pathology and is accompanied by broad disruptions in proteostasis. Heat shock proteins (HSPs) help maintain proteostasis, yet mitochondrial chaperone systems remain comparatively underexplored in AD. Hsp60 and Hsp10 form a mitochondrial chaperonin complex that folds dozens of AD-implicated mitochondrial proteins, but this client network has not been evaluated as an integrated proteostasis axis in AD. It remains unknown whether Hsp60/10 client proteins are selectively vulnerable across AD severity. MethodsWe analyzed transcriptomic, proteomic, neuropathological, and cognitive data from the Religious Order Study and Memory and Aging Project (ROSMAP) to evaluate Hsp60/10 client proteins in AD. We compared Hsp60/10 clients with abundance-matched non-client mitochondrial proteins and tested differences across AD diagnostic groups and associations with Braak/tau burden, cognitive outcomes, and network centrality. These evidence layers were integrated into a candidate prioritization framework. ResultsHsp60/10 client abundance declined more strongly at the protein level than at the RNA level in late-stage AD. Compared with abundance-matched non-client mitochondrial proteins, Hsp60/10 clients showed stronger late-stage protein abundance decline. Greater late-stage client decline was associated with higher Hsp60/10 network centrality, defining a selectively vulnerable client subnetwork. Lower client abundance was associated with greater Braak/tau burden and greater cognitive impairment. Integrated prioritization nominated mitochondrial translation and TCA/pyruvate/redox clients as high-priority candidates for mechanistic follow-up. ConclusionsTogether, these findings identify an Hsp60/10 client-centered mitochondrial proteostasis axis spanning mitochondrial translation and TCA/pyruvate/redox metabolism that is associated with AD severity. These findings identify a novel potential axis warranting further investigation as a mechanistic link between mitochondrial dysfunction, proteostasis, and AD.

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Sloane, A., Kattunga, V. M., Andersen, J. K.. 2026-06-30. Mitochondrial Hsp60/10 Client Protein Decline Reveals Braak/Tau- and Cognition-Linked Proteostasis Vulnerabilities in Alzheimer's Disease. https://doi.org/10.64898/2026.06.25.734545

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