PRESERVED STRIATAL NEURONS DESPITE IMPAIRED OXPHOS IN ARGINASE 2 KNOCKOUT MICE. PROTECTION VIA METABOLIC REPROGRAMMING?

Arginase 2 (Arg2) is a mitochondrial enzyme involved in arginine metabolism. It is particularly enriched in the striatum, where it localizes to medium spiny neurons (MSNs), and its impairment accompanies neurodegeneration in Huntington’s disease. Our studies demonstrated that the absence of Arg2 affects striatal metabolism, and hypothesized that Arg2 loss may induce MSNs death through impairment of mitochondria, an important hub in cellular metabolism and critical contributor to neurodegeneration.
Experiments were performed using Arg2 knockout (KO) mice. Striatal proteomes were analyzed by LC–MS. Mitochondrial ultrastructure was assessed by TEM, and mitochondrial complex assembly was examined by BN-PAGE. COX/SDH staining as well as NADH/NAD⁺, and ATP/ADP assays were performed to further evaluate cellular energy parameters. ROS production was measured using DHE and IVIS imaging, and MSNs number was estimated using stereology. Data analysis was performed using ZEISS ZEN, GraphPad Prism 10.6, ImageJ, Cellpose, Perseus, R, and STRING.
In the Arg2 KO striatum, proteins associated with OXPHOS and neurodegeneration were altered. Neuronal mitochondria exhibited structural abnormalities, including swelling, disrupted cristae, and outer membrane damage. Levels of complexes I, III, and IV were reduced, without subcomplex formation, and complex I activity was decreased. Arg2 KO striata exhibited increased ROS and a decreased NADH/NAD⁺ ratio, whereas ATP/ADP ratio was unaltered and the MSNs number remained unchanged.
We conclude that the absence of Arg2 results in impaired OXPHOS in MSNs, however the cells remain functional and viable, likely due to metabolic reprogramming toward compensatory energy sources.