Mitochondrial Network Enhancing (MiNE) Nanoparticles for the Treatment of Neurodegenerative Disease and the Aging Brain

There is a current surge in the global occurrence of neurodegenerative diseases (ND), a collection of age-related diseases highly associated with mitochondrial dysfunction. Mitochondria supply cellular energy (depleted in ND), mediate cell death (which is premature in ND), and rescue cells from the unfolded protein response (accumulation of misfolded proteins is associated with ND). Mitochondrial Network Enhancing (MiNE) nanoparticles (NPs) have been designed to correct mitochondrial dysfunction in ND by increasing mitochondrial networks and increasing the fusion of mitochondria to the endoplasmic reticulum (ER). Nanoparticles encapsulating a pro-Mitofusin 2 (MFN2) peptide were synthesized and characterized for size, zeta potential, and drug loading efficiency. MFN2 mediates mitochondrial fusion and mitochondrial-ER fusion. Live cell microscopy of MiNE NP and control treated primary hippocampal neurons and NIH3T3 fibroblasts at 60X was performed and images were processed using mitochondrial network analysis software to quantify changes in mitochondrial networks. Mitochondrial-ER co-localization studies were performed along with an unfolded protein response study and an oxidative phosphorylation assay. Treatment with MiNE NPs increases mitochondrial networks and increases mitochondrial-ER co-localization. MiNE NPs increase the cellular capacity for oxidative phosphorylation which could increase energy efficiency in ND. Importantly, MiNE NPs protect against the unfolded protein response which could decrease the accumulation of misfolded proteins in ND. MiNE NPs are a novel translational nanomedicine for treating ND by targeting the intersection of mitochondria and the ER. These preliminary studies of MiNE NPs validate further evaluation of MiNE NPs as a promising treatment for ND and as an anti-aging strategy. Mitochondria are organelles (sub-cellular components) that control energy production, mediate cell death, and can prevent the accumulation of misfolded proteins in cells. Neurodegenerative disease (ND) is characterized by energy depletion, premature death of neurons, and an accumulation of misfolded proteins in the brain. Mitochondrial Network Enhancing (MiNE) nanoparticles (NPs) are a novel treatment for ND that corrects for mitochondrial dysfunction in ND by increasing mitochondrial networks and increasing the ability of mitochondria to network with the endoplasmic reticulum, the part of the cell that produces and folds proteins. Preliminary studies demonstrate the promise of MiNE NPs as a novel treatment for ND. The application of MiNE NPs in treating progeria (accelerated aging diseases) will also be explored. The primary focus of future studies is the in vivo evaluation of MiNE NPs administered via intranasal delivery in animal models of ND.