IMPACT OF SORL1 DEFICIENCY ON MITOCHONDRIAL DYNAMICS, CALCIUM HANDLING AND OXIDATIVE STRESS IN ALZHEIMER’S DISEASE

Mutations in the SORL1 gene are associated with early-onset Alzheimer’s disease (AD) and constitute a genetic risk factor for sporadic late-onset AD. Reduced levels of Sorl1, encoded by the SORL1 gene, have been reported in post-mortem AD brains and patient-derived cells, and increasing evidence links Sorl1 deficiency to mitochondrial dysfunction. Sorl1 is highly enriched at mitochondria-associated membranes (MAMs), key sites for metabolic exchange between the endoplasmic reticulum and mitochondria, including calcium (Ca²⁺) transfer. Given the central role of mitochondria in bioenergetics, redox balance, Ca²⁺ homeostasis, and cell survival, alterations in these processes may contribute to neurodegeneration. In this study, we investigated the impact of Sorl1 deficiency on mitochondrial dynamics, mitophagy, Ca²⁺ homeostasis, oxidative stress, and cell viability using fibroblasts from AD patients carrying SORL1 mutations and SH-SY5Y neuroblastoma cells with stable SORL1 knockdown. We observed unbalanced mitochondrial fusion and fission which was accompanied by enhanced mitophagy, as evidenced by the accumulation of mitochondria within lysosomal compartments. In parallel, Sorl1-deficient cells exhibited altered intracellular Ca²⁺ flux. These alterations were associated with a tendency toward increased mitochondrial and cytosolic reactive oxygen species production and reduced cellular viability. Overall, our findings indicate that Sorl1 deficiency disrupts mitochondrial dynamics and mitophagy, together with intracellular Ca²⁺ handling, leading to oxidative stress and impaired cell survival. These mechanisms may contribute to neuronal vulnerability in AD and highlight Sorl1-related pathways as potential therapeutic targets.