EXPLORING THE RELATIONSHIP BETWEEN RTP801 AND MITOCHONDRIAL DYNAMICS IN NEURODEGENERATION

Neurodegenerative diseases are characterized by mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. RTP801/REDD1 is a stress-responsive regulator of cellular metabolism and survival pathways that contributes to neuroinflammation and cognitive deficits in neurodegeneration. RTP801 has also been reported to modulate mitochondrial homeostasis by disrupting mitochondrial-associated membranes, affecting bioenergetic coupling and ATP production. However, whether and how RTP801 influences mitochondrial integrity and function in neurons and its effects in neurodegeneration remains unexplored.
Here we wanted to investigate the role of RTP801 in modulating mitochondrial dynamics and neuronal vulnerability under physiological and pathological conditions. Primary mouse cortical neurons overexpressing RTP801 were used to assess mitochondrial organization. Immunofluorescence analysis revealed that increased RTP801 levels are associated with elevated mitochondrial density and marked alterations in mitochondrial morphology and network architecture, characterized by a shift toward a more fragmented population with reduced elongation and interconnectivity. Consistently, machine learning–based morphological classification identified a modest increase in fragmented mitochondria and corresponding decrease in elongated and networked structures following RTP801 overexpression.
Complementary proteomic analyses of mouse hippocampi indicate that RTP801 silencing in the 5xFAD model of Alzheimer’s disease prevents the alteration of crucial mitochondrial proteins. Ongoing studies integrate functional and bioenergetic analyses, including mitochondrial respiration profiling, to define the impact of RTP801 modulation on mitochondrial performance and neuronal health.
Collectively, these findings suggest a functional link between RTP801 and mitochondrial dysfunction which could contribute to neuronal vulnerability in neurodegeneration.