Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer's disease

Abstract

Mitochondrial dysfunctions are supposed to be responsible for many neurodegenerative diseases dominating in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). A growing body of evidence suggests that defects in mitochondrial metabolism and particularly of electron transport chain may play a role in pathogenesis of AD. Structurally and functionally damaged mitochondria do not produce sufficient ATP and are more prominent in producing proapoptotic factors and reactive oxygen species (ROS), and this can be an early stage of several mitochondrial disorders, including neurodegenerative diseases. Mitochondrial dysfunctions may be caused by both mutations in mitochondrial or nuclear DNA that code mitochondrial components and by environmental causes. In the following review, common aspects of mitochondrial impairment concerned about neurodegenerative diseases are summarized including ROS production, impaired mitochondrial dynamics, and apoptosis. Also, damaged function of electron transport chain complexes and interactions between pathological proteins and mitochondria are described for AD particularly and marginally for PD and HD.

Figure 1

Mitochondrial dysfunctions in Alzheimer's disease. Amyloid-beta (Aβ) impairs the integrity of cytoplasmic membrane and causes mitochondrial dysfunctions. Aβ inhibits the activity of oxidative phosphorylation (OXPHOS) system, which can result in decrease of ATP production and increased reactive oxygen species (ROS) formation. Decreased ATP production leads to impairment of ATP-dependent processes, where all cellular functions are involved. Decrease of mitochondrial membrane potential (Δψ _m) is followed by opening of mitochondrial permeability transition pores (MPTPs). Release of cytochrome c (cyt c) and other proapoptotic factors from the intermembrane space of mitochondria induces the formation of apoptosome and consequently triggers activation of caspases and apoptosis. Apoptosis inducing factor (AIF) is a proapoptotic factor released by mitochondria. Disengaged AIF is transported into nucleus and triggers caspases-independent apoptosis. Phosphorylated tau protein (pTau) and Aβ cause enhanced nitrosylation of dynamin-related protein-1 (Drp1) leading to impaired mitochondrial dynamics, increased mitochondrial fission, and neurodegeneration. Further, Aβ inhibits the import of proteins into mitochondria and reduces activity of mitochondrial amyloid-beta binding alcohol dehydrogenase (ABAD), α-ketoglutarate dehydrogenase complex (α-KGDH), and cyclophilin D. Ability of mitochondria to handle Ca²⁺ is impaired by Aβ and Aβ precursor protein (APP); consequently overload of mitochondrial calcium leads to decrease of Δψ _m, opening of MPTPs, releasing of proapoptotic factors, increased ROS production, and decreased ATP production. PGC-1—peroxisome proliferator-activated receptor-gamma coactivator-1-alpha; TIM—translocase of the inner membrane; TOM—translocase of the outer membrane.