The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer's Disease Pathology

Abstract

Current shreds of evidence point to the entorhinal cortex (EC) as the origin of the Alzheimer's disease (AD) pathology in the cerebrum. Compared with other cortical areas, the neurons from this brain region possess an inherent selective vulnerability derived from particular oxidative stress conditions that favor increased mitochondrial molecular damage with early bioenergetic involvement. This alteration of energy metabolism is the starting point for subsequent changes in a multitude of cell mechanisms, leading to neuronal dysfunction and, ultimately, cell death. These events are induced by changes that come with age, creating the substrate for the alteration of several neuronal pathways that will evolve toward neurodegeneration and, consequently, the development of AD pathology. In this context, the present review will focus on description of the biological mechanisms that confer vulnerability specifically to neurons of the entorhinal cortex, the changes induced by the aging process in this brain region, and the alterations at the mitochondrial level as the earliest mechanism for the development of AD pathology. Current findings allow us to propose the existence of an altered allostatic mechanism at the entorhinal cortex whose core is made up of mitochondrial oxidative stress, lipid metabolism, and energy production, and which, in a positive loop, evolves to neurodegeneration, laying the basis for the onset and progression of AD pathology.

Keywords: ATP synthase; aging; energy metabolism; entorhinal cortex; lipoxidation-derived damage; mitochondrial dysfunction; neurodegeneration; oxidative damage.

Figure 1

Progression and spread of Alzheimer’s disease in humans based on tau (NFTs) and β-amyloid (SPs) as a neuropathological reference. (A) Progression of tau pathology (Braak staging), and (B) progression of β-amyloid pathology (β-amyloid deposits). For details, see main text. Reproduced and modified with permission from [40].

Figure 2

High longevity and morphological complexity are traits that confer selective vulnerability to neurons in layer II of the medial and lateral entorhinal cortex in humans. For details, see main text. Reproduced and modified with permission from [58].

Figure 3

The triad formed by the activity of the mitochondrial electronic transport chain, the lipid profile, and the activity of ATP synthase constitutes the basic component whose alteration at the level of the neurons of the entorhinal cortex gives rise to the origin and subsequent progression of Alzheimer’s disease pathology.

Figure 4

Structure of the mitochondrial F0F1 ATP synthase (complex V) in mammals. Human mitochondrial ATP synthase is a protein complex composed of 28 subunits and organized into two domains: a membrane-embedded F0 domain, and a membrane-extrinsic and matrix-oriented F1 catalytic domain. The two domains are connected by a peripheral and central stalk. For additional structural and functional details see [147,148]. Functionally, the F0 domain is a trans-membrane channel that translocates protons and F1, a synthase domain that binds to ADP and inorganic phosphate and synthesizes ATP. ATP synthase is also involved in mitochondrial cristae formation, as well as in the formation of the permeability transition pore (PTP), which triggers cell death. Importantly, some of the functional properties of ATP synthase and regulatory mechanisms are associated with the integrity of specific residues such as cysteine, arginine, and lysine [150]. Thus, for instance, specific post-translational modifications play important roles in ATP synthase regulation by modifying ε-amino groups of lysine, with the resulting conformational changes of the active sites and decreased enzymatic activity. Similarly, the integrity of structural lysine residues is a key point to promote interaction with membrane lipids, particularly cardiolipin, in order to ensure correct ATP synthase activity [150]. The oxidative and lipoxidative non-enzymatic modificationm—ediated by reactive oxygen species (ROS) and carbonyl species (RCS), respectively—of ATP synthase observed during early stages of AD pathology mostly and preferentially affects the α and β subunits. Reproduced and modified with permission from [147].

Figure 5

Interactome map of deregulated proteins in the EC of AD at III–IV stage. Edge colors: (i) protein level correlations of proteomic data obtained by Orbitrap Velos, and (ii) interactions retrieved from the public databases BIND, CCSB, DIP, GRID, PubMed, Reactome, KEGG, HPRD, IntAct, MDC, and MINT. Node colors indicate cellular components provided by GO. A large cluster in the center corresponds to deregulated mitochondria-related proteins. Reproduced and modified with permission from [144].