Mitochondrial Medicine: A Promising Therapeutic Option Against Various Neurodegenerative Disorders

Abstract

Abnormal mitochondrial morphology and metabolic dysfunction have been observed in many neurodegenerative disorders (NDDs). Mitochondrial dysfunction can be caused by aberrant mitochondrial DNA, mutant nuclear proteins that interact with mitochondria directly or indirectly, or for unknown reasons. Since mitochondria play a significant role in neurodegeneration, mitochondriatargeted therapies represent a prosperous direction for the development of novel drug compounds that can be used to treat NDDs. This review gives a brief description of how mitochondrial abnormalities lead to various NDDs such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We further explore the promising therapeutic effectiveness of mitochondria- directed antioxidants, MitoQ, MitoVitE, MitoPBN, and dimebon. We have also discussed the possibility of mitochondrial gene therapy as a therapeutic option for these NDDs.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; gene therapy; mitochondrial dysfunction.

Fig. (1)

Structure and OXPHOS of the mitochondria. (A) Mitochondria is a cellular organelle that play role in multiple cellular processes. Structurally, mitochondria have two membranes the outer and inner membrane. Both membranes are separated by an intermembrane space. The outer membrane separates the mitochondria from the cell cytoplasm while the inner membrane separates the matrix from intermembrane space. Inner membrane is differentiated and extend into the matrix forming cristae. (B) Membrane bound electron transport chain in addition to complex V are responsible for ATP production through OXPHOS. The process involves electron flow from complex I, complex II, complex III, complex VI, and complex V. Created with BioRender.com.

Fig. (2)

Mitochondrial dynamics. Mitochondria are very dynamic organelle that go through fission and fusion. Fission or mitochondria division can occur once Drp1 forms a ring around the mitochondria once recruited by Fis1, MID49, and MID51. Fusion or fuse of two mitochondria together occurs once multiple OMM proteins MFN1/2 and OPA1 are recruited to the surface of the mitochondria. Created with BioRender.com.

Fig. (3)

Mitochondrial medicines. Antioxidants maintain redox balance and decrease the stress level by avoiding damage of lipids, proteins, and DNA; Dimebon inhibits glutamate inflow by binding to NMDA receptors on the cell's surface. It also binds to Ca²⁺ channels, preventing a Ca²⁺ influx into the cell; Triphenylphosphonium cation-based antioxidants like MitoQ. MitoPBN etc. could be used to deliver antioxidants to the inside of the mitochondria; cyclosporin A (CsA) inhibits mitochondrial permeability transition pore (mPTP). Created with BioRender.com.