Q-Der: A Next-Generation CoQ10 Analogue Supercharging Neuroprotection by Combating Oxidative Stress and Enhancing Mitochondrial Function

Michela Battistelli ^1* Matteo Micucci ¹ Federico Gianfanti ¹ Sabrina DONATI ZEPPA ¹ Giosuè Annibalini ¹ BARBARA CANONICO ¹ fabiana fanelli ¹ ROBERTA SALTARELLI ¹ riham osman ¹ mariele montanari ¹ daniele lopez ¹ gemma nasoni ¹ Giovanna Panza ¹ Erik Bargagni ¹ Francesca Luchetti ¹ Michele Retini ¹ Michele Mari ¹ Giovanni Zappia ² Vilberto Stocchi ² Alessia Bartolacci ¹ Sabrina Burattini ¹

• ¹ University of Urbino Carlo Bo, Urbino, Italy
• ² Department of Human Science and Promotion of Quality of Life, San Raffaele Telematic University, Rome, Lazio, Italy

Background: Mitochondrial dysfunction and oxidative stress are central mechanisms in the progression of neurodegenerative diseases. This study first evaluated the toxicity of Q-Der (Q10-diacetate), a derivative of Coenzyme Q10, in HT22 hippocampal neurons under normal and oxidative stress conditions. Methods: HT22 cells were treated with Q-Der at 2.5, 5 and 10 µM with and without rotenone. Mitochondrial superoxide production (Mitosox), gene expression (via qRT-PCR), and protein levels (via Western blot) were measured. Morphological analyses were performed using transmission (TEM) and scanning (SEM) electron microscopes. Results: Q-Der significantly reduced mitochondrial superoxide levels, particularly at 5 µM, and upregulated key mitochondrial biogenesis genes, including PGC-1α and TFAM. Additionally, it restored the expression of MT-ND1 and MT-COI, which were downregulated by rotenone. Western blot results showed a significant recovery in CV-ATP5A (complex V) expression (p < 0.05), preserving mitochondrial ATP production. Morphological analyses further confirmed Q-Der's ability to maintain cellular and mitochondrial structure under stress conditions. Conclusions: These findings suggest that Q-Der is nontoxic under normal conditions and protects against oxidative stress, supporting its potential as a therapeutic agent for neurodegenerative diseases.