The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency
Year: 2026
Type: article
Abstract: KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated neuronal loss in the brainstem, diminished activation of astrocytes, blocked hypertrophic microglial accumulation, and reduced reactive oxygen species (ROS) levels in the brain. NV354 also partially alleviated motor symptoms and metabolic decompensation in a rat model of Parkinson disease induced by the CI inhibitor rotenone. In conclusion, the succinate prodrug NV354 shows promise as a potential treatment of mitochondrial CI-related neurodegeneration.
Source: iScience
Authors: Meagan J. McManus, Yi Zhu, Cesar Alves, Neha Kohli, Patricia Prada-Dacasa, Laura Sanchez-Benito, Elisenda Sanz, Irene Yee, Lozen Robinson, Malkah Sheldon, Walter J. McHugh, Abhay Ranganathan, Jennie Meng, Nina Duncan, Alvar Grönberg, Douglas C. Wallace, Sarah Piel, Michael Karlsson, Steven J. Moss, Lee Webster, Magnus J. Hansson, Eskil Elmér, Johannes K. Ehinger, Albert Quintana, Todd J. Kilbaugh
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
OpenAlex ID: W7124442920