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

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 Aβ1-42-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 Aβ1-42 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, Aβ1-42 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, Aβ1-42 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.