Dysfunctional mitophagy in Alzheimer's disease: evidence from peripheral Optineurin.

Authors

Simone Patergnani, Alessandro Trentini, Valentina Rosta, Paola Guindani, Alessandro Greatti, Dario Pedrini, Giorgia Meneguzzo, Leonardo Rigon, Nicola Filippini, Elena Giusto, Giovanni Zuliani, Paolo Pinton, Carlo Cervellati

Published in

Free radical biology & medicine. Sep 19, 2026. Epub Sep 19, 2026.

Abstract

Mitophagy and mitochondrial quality-control pathways are impaired in Alzheimer's disease (AD), but the relevance of peripheral mitophagy markers and their regulation during sustained amyloid-β (Aβ) stress remain unclear. We investigated whether serum optineurin, a mitophagy receptor, is altered in mild cognitive impairment (MCI) and AD, and explored mitophagy dynamics in an in vitro model of Aβ_1-42-induced mitochondrial stress. To achieve this aim, serum optineurin was measured in 458 older individuals, including controls and patients with AD, mild cognitive impairment (MCI), and mixed Alzheimer's disease/ vascular dementia (MIXED). Complementary in vitro experiments were performed in SH-SY5Y neuroblastoma cells exposed to Aβ_1-42 over time, to evaluate mitochondrial function, oxidative stress, lipid peroxidation, lactate release, Parkin/optineurin recruitment, mitophagy, mitochondrial quality-control markers, apoptosis, and cell viability. Serum optineurin was markedly lower in MCI and AD groups than in controls (p < 0.001 for both) and was also reduced in MIXED (p < 0.001). Serum 4-HNE was increased in MCI and AD, consistent with systemic oxidative stress. In vitro, Aβ_1-42 induced an early increase in mitophagy and optineurin expression, followed by a later decline associated with impaired mitochondrial quality-control markers, apoptotic activation, and reduced cell viability. In conclusion, optineurin emerges as a candidate peripheral biomarker associated with AD and MCI. In vitro, Aβ_1-42 exposure was associated with an early increase in mitophagy-related responses followed by progressive mitochondrial dysfunction, oxidative stress, apoptotic activation, and reduced cell viability. These findings support the relevance of optineurin within mitochondrial quality-control pathways under AD-related stress.

PMID:
42763018
Bibliographic data and abstract were imported from PubMed on 20 Sep 2026.

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