The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency

TL;DR

A new succinate prodrug called NV354 shows potential in preventing brain damage and motor issues in mitochondrial disease models.

Contribution

NV354 is a novel succinate prodrug with brain-penetrating properties that shows therapeutic potential in mitochondrial complex I deficiency.

Findings

NV354 prevents brainstem lesions and neuronal loss in a mouse model of Leigh syndrome.

The prodrug reduces oxidative stress and neuroinflammation in the brain.

NV354 partially alleviates motor symptoms in a Parkinson disease model induced by rotenone.

Abstract

Leigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 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.

•Succinate prodrug prevents brain lesions and motor dysfunction in mitochondrial disorders•Succinate prodrug reduces oxidative stress and neuroinflammation in mice•Therapeutic effects observed in complex I deficiency and Parkinson disease models•Succinate prodrugs may provide a novel treatment for mitochondrial disorders

Succinate prodrug prevents brain lesions and motor dysfunction in mitochondrial disorders

Succinate prodrug reduces oxidative stress and neuroinflammation in mice

Therapeutic effects observed in complex I deficiency and Parkinson disease models

Succinate prodrugs may provide a novel treatment for mitochondrial disorders

Natural sciences; biological sciences; biochemistry; neuroscience

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