Mechanisms of Mitochondrial Dysfunction in Alzheimer’s Disease

Abstract

Mitochondria are the primary source for energy generation in the cell, which manifests itself in the form of the adenosine triphosphate (ATP). Nicotinamide dinucleotide (NADH) molecules are the first to enter the so-called electron transport chain or ETC of the mitochondria. The ETC represents a chain of reducing agents organized into four major protein-metal complexes (I-IV) that utilize the flow of electrons to drive the production of ATP. An additional integral protein that is related to oxidative phosphorylation is ATP synthase, referred to as complex V. Complex V carries out ATP synthesis as a result of the electron flow through the ETC. The coupling of electron flow from NADH to molecular oxygen to the production of ATP represents a process known as oxidative phosphorylation. In this review, we describe mainly the bioenergetic properties of mitochondria, such as those found in the ETC that may be altered in Alzheimer's disease (AD). Increasing evidence points to several mitochondrial functions that are affected in AD. Furthermore, it is becoming apparent that mitochondria are a potential target for treatment in early-stage AD. With growing interest in the mitochondria as a target for AD, it has been hypothesized that deficit in this organelle may be at the heart of the progression of AD itself. The role of mitochondria in AD may be significant and is emerging as a main area of AD research.

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“…Characterized by extracellular β-amyloid plaque (in particular formed by Aβ 1–42 peptide) and neurofibrillary tangles within neurons, the vast majority of drug development for the treatment of AD has been based on the hypothesis that it is an excess of cerebral Aβ that triggers a cascade of events that include mitochondrial dysfunction, oxidative stress, and neuroinflammation that lead to neuronal dysfunction and ultimately neuronal death (Behl and Holsboer, 1998; Cadonic et al, 2015; Griffin and Mrak, 2002; Heneka and O’Banion, 2007; Simonian and Coyle, 1996). …”

“…Mitochondria are highly dynamic with morphology and number regulated by the balance between fission and fusion proteins (Itoh et al, 2013). Aberrant mitochondrial fragmentation resulting from imbalance in the fusion-fission process leading to impaired mitochondrial function and neuronal death, are pathological findings in many neurodegenerative disorders including AD (Cadonic et al, 2015), and may represent a seminal event in the pathway leading to neurodegeneration. In line with this concept, compelling studies have pointed to the negative alterations of mitochondrial function at early stages of AD, including mitochondrial dynamic imbalance mediated by elevated ratios of fission over fusion proteins, massive megapore formation, enhanced autophagy activity, reduced anti-oxidant capacity, and failed adenosine triphosphate (ATP) production (Burte et al, 2015; Cabezas-Opazo et al, 2015; Grimm et al, 2016).…”