Mitochondria as a therapeutic target for aging and neurodegenerative diseases

Abstract

Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative phosphorylation, increased accumulation of mitochondrial DNA defects, impaired calcium influx, accumulation of mutant proteins in mitochondria, and mitochondrial membrane potential dissipation are important cellular changes in both early and late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and neurodegenerative diseases. This paper discusses research that elucidates features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases and discusses mitochondrial structural and functional changes, and abnormal mitochondrial dynamics in neurodegenerative diseases. It also outlines mitochondria-targeted therapeutics in neurodegenerative diseases.

Figure 1

Factors those are critical for healthy and extended lifespan in humans.

Figure 2. Structure of mitochondria

Mitochondria are bag like structures, comprised of 2 lipid membranes (outer and inner), and matrix that harbor components of tricarboxylic acid cycle, beta-oxidation. The electron transport chain is localized in the inner mitochondrial membrane. Outer mitochondrial membrane is porous, whereas mitochondrial inner membrane restricts ionic flow and protects the contents of matrix. Mitochondrial ATP is generated via oxidative phosphorylation within the inner mitochondrial membrane. Free radicals are generated as a byproduct of oxidative phosphorylation, primarily due to electron leaks in complex I and III of respiratory chain. The components of tricarboxylic acid, including α-ketoglutarate dehydrogenase, generate superoxide radicals in the matrix. These mitochondrially generated free radicals and superoxide radicals are carried to the cytoplasm via voltage-dependent anion channels and participate in lipid peroxidation, and protein and DNA oxidation.

Figure 3. Localization of mutant proteins of AD in the mitochondria in neurons affected by AD

In early-onset AD, genetic mutations of APP, PS1 and PS2 genes activate beta and gamma secretases, cleave from c-terminal region of amyloid beta precursor protein, and produce Aβ peptides. The toxic Aβ peptides enter mitochondria, interact with mitochondrial proteins, including cyclophilin D and ABAD --induce free radicals, decrease cytochrome oxidase activity, inhibit ATP generation and damage mitochondria both structurally and functionally. Further, in late-onset AD, APP is transported to outer mitochondrial membrane, blocks the import of nuclear cytochrome oxidase proteins to mitochondria and may be responsible for decreased cytochrome oxidase activity. In addition, N-terminal portion of ApoE4 is associated with mitochondria, induce free radicals and cause oxidative damage. In AD, complex IV of mitochondrial respiratory chain is affected.

Figure 4. The association of mutant huntingtin with mitochondria of HD neurons

In HD neurons, mutant Htt binds to outer mitochondrial membrane and induces free radical production, and may interrupt with calcium uptake. In HD, complex II of mitochondrial respiratory chain is affected.

Figure 5. Localization of mutant proteins of PD in the mitochondria in neurons affected by PD

In PD neurons, mutant proteins of α-synuclein, parkin, PINK1, and DJ1 are associated with mitochondria and cause mitochondrial dysfunction. Complex I activity is inhibited in PD neurons.

Figure 6. Localization of mutant proteins of SOD1 in the mitochondria in neurons affected by ALS

In ALS, mutant SOD1 is localized to inner, outer mitochondrial membranes, intermembrane space and matrix, and induce free radical production and oxidative damage. Impairment of Complex II and IV are associated with ALS.