Nanotechnology-Based Drug Delivery Strategies to Repair the Mitochondrial Function in Neuroinflammatory and Neurodegenerative Diseases

Abstract

Mitochondria are vital organelles in eukaryotic cells that control diverse physiological processes related to energy production, calcium homeostasis, the generation of reactive oxygen species, and cell death. Several studies have demonstrated that structural and functional mitochondrial disturbances are involved in the development of different neuroinflammatory (NI) and neurodegenerative (ND) diseases (NI&NDDs) such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Remarkably, counteracting mitochondrial impairment by genetic or pharmacologic treatment ameliorates neurodegeneration and clinical disability in animal models of these diseases. Therefore, the development of nanosystems enabling the sustained and selective delivery of mitochondria-targeted drugs is a novel and effective strategy to tackle NI&NDDs. In this review, we outline the impact of mitochondrial dysfunction associated with unbalanced mitochondrial dynamics, altered mitophagy, oxidative stress, energy deficit, and proteinopathies in NI&NDDs. In addition, we review different strategies for selective mitochondria-specific ligand targeting and discuss novel nanomaterials, nanozymes, and drug-loaded nanosystems developed to repair mitochondrial function and their therapeutic benefits protecting against oxidative stress, restoring cell energy production, preventing cell death, inhibiting protein aggregates, and improving motor and cognitive disability in cellular and animal models of different NI&NDDs.

The role of mitochondrial dynamics in disease

“…However, in podocytes DRP1 phosphorylation at Ser637/656 promotes mitochondrial fission due to high glucose conditions, 9,35 and Ser600 phosphorylation by PKA decreases DRP1 GTPase activity 36 . In a study published in 2021, DRP1 phosphorylation at Ser637 was shown to promote subsequent Ser616 phosphorylation, and only blocking downstream Ser616 phosphorylation leads to mitochondrial elongation rather than fission 37 . In mouse embryonic fibroblasts, phosphorylation at both sites is essential for maximal fission, indicating that phosphorylation at Ser637 promotes fission or fusion and this function depends on Ser616 phosphorylation status 37 .…”

“… 36 In a study published in 2021, DRP1 phosphorylation at Ser637 was shown to promote subsequent Ser616 phosphorylation, and only blocking downstream Ser616 phosphorylation leads to mitochondrial elongation rather than fission. 37 In mouse embryonic fibroblasts, phosphorylation at both sites is essential for maximal fission, indicating that phosphorylation at Ser637 promotes fission or fusion and this function depends on Ser616 phosphorylation status. 37 SUMO1, SUMO2, or SUMO3 have opposite effects on DRP1 activity.…”

“… 37 In mouse embryonic fibroblasts, phosphorylation at both sites is essential for maximal fission, indicating that phosphorylation at Ser637 promotes fission or fusion and this function depends on Ser616 phosphorylation status. 37 SUMO1, SUMO2, or SUMO3 have opposite effects on DRP1 activity. SUMO2 and SUMO3 reduce DRP1 association with OMM, 38 whereas the conjugation of SUMO1 promotes DRP1 binding, 39 DRP1 posttranslational modifications are clearly complex and exist depending on the cellular context.…”

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence

“…MS is an autoimmune disease which is not fully understood, likely has multiple distinct causes, and is not considered a genetic mitochondrial disease; however, in MS occurs much more often with LHON than would occur by chance in Harding's syndrome, and in this situation the MS symptoms can be putatively causally linked to the mitochondrial defect driving the LHON pathology [39,40]. MS has been causally linked to inflammation, while evidence increasingly supports a role for mitochondrial dysfunction [41][42][43]. Harding's syndrome provides an example of a disease clearly linked to both mitochondrial defects and inflammation.…”

Common methods in mitochondrial research (Review)

“…To treat primary mitochondrial diseases, gene therapy based on ectopic expression is still the first choice; however, the application of viral vectors in live animals to correct any gene mutation still has the following significant problems: High cost (390,(412)(413)(414)(415), carcinogenicity and immunogenicity. Non-viral vector-mediated in situ mitochondrial gene therapy may be a promising approach to overcome the bottleneck of existing gene therapy LHON, such as liposome-based nanoparticles, which require further investigation (416)(417)(418)(419)(420)(421).…”