TARGETING MITOCHONDRIAL DYSFUNCTION IN LYSOSOMAL STORAGE AND OTHER NEURODEGENERATIVE DISORDERS

Growing evidence implicates mitochondrial dysfunction as a key driver of neurodegeneration in several diseases, including the “juvenile Alzheimer’s” Niemann Pick C1 (NPC1)1, a cholesterol lysosomal storage disorder, where inflammation contributes to neuronal loss2. Our findings indicate that mitochondrial cholesterol depletion impairs respiratory complexes and elevates ROS3, partly via downregulating Mnrr1 and antioxidant genes. Mnrr11 (Chchd2) is a key regulator of organelle function4, acting in mitochondria to control metabolism and apoptosis, and in the nucleus to activate stress-responsive genes, including itself. Its deficiency phenocopies NPC1 pathology by reducing oxidative metabolism, ATP production, and cell growth while increasing ROS. Moreover, Mnrr1 is required for mitophagy and the mitochondrial unfolded protein response. Mnrr1 overexpression reduces cholesterol accumulation and improves mitochondrial function in cells harboring common Npc1 mutations. We are investigating the impact of drug-induced Mnrr1 overexpression in cellular models of NPC1 disease: we hypothesize that increased Mnrr11 expression could reduce neuroinflammation and reverse metabolic deficits caused by cholesterol dyshomeostasis. Our data show that the metabolic modulator nitazoxanide (NTZ) improves mitochondrial function by stabilizing organelle membrane potential, reducing ROS generation, and optimizing oxidative phosphorylation5;6. Additionally, NTZ significantly raises CoxIV expression and recovers Mnrr1 protein levels, with a noticeable perinuclear accumulation suggesting enhanced mitochondrial integrity and function. Meanwhile, NTZ decreases Mtor1, Ampk-α, and p62 protein expression, suggesting a coordinated modulation of autophagy-regulating pathways that may aid in restoring organelle quality control. Thus, NTZ seems to be a mitochondrial resilience enhancer that may repair critical quality control and bioenergetic systems that have been seriously harmed in NPC1. 110.1038/s41586-024-07167-9 210.1016/j.bbalip.2004.08.011 310.1016/j.mito.2019.12.003 410.1155/2017/6739236 510.1074/jbc.M117.791863 610.1016/j.cellsig.2023.110769