Dynamic Interplay between Copper Toxicity and Mitochondrial Dysfunction in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, affecting millions of people worldwide, a number expected to exponentially increase in the future since no effective treatments are available so far. AD is characterized by severe cognitive dysfunctions associated with neuronal loss and connection disruption, mainly occurring in specific brain areas such as the hippocampus, cerebral cortex, and amygdala, compromising memory, language, reasoning, and social behavior. Proteomics and redox proteomics are powerful techniques used to identify altered proteins and pathways in AD, providing relevant insights on cellular pathways altered in the disease and defining novel targets exploitable for drug development. Here, we review the main results achieved by both -omics techniques, focusing on the changes occurring in AD mitochondria under oxidative stress and upon copper exposure. Relevant information arises by the comparative analysis of these results, evidencing alterations of common mitochondrial proteins, metabolic cycles, and cascades. Our analysis leads to three shared mitochondrial proteins, playing key roles in metabolism, ATP generation, oxidative stress, and apoptosis. Their potential as targets for development of innovative AD treatments is thus suggested. Despite the relevant efforts, no effective drugs against AD have been reported so far; nonetheless, various compounds targeting mitochondria have been proposed and investigated, reporting promising results.

Keywords: Alzheimer disease; copper; mitochondria; oxidative stress; proteomics; redox proteomics.

Figure 3

Structures of ETC complex I (a), III (b), and IV (c). Dysregulated and oxidatively modified subunits are evidenced in all complexes. The Protein Data Bank (PDB) codes of the structural models are 5XTD [47], for complex I (human), 5XTE [47], for complex III (human), and 5Z62 [48], for complex IV (human).

Figure 1

Schematic representation of the interplay between mitochondria activity, copper induced ROS generation and Aβ aggregates.

Figure 2

Schematic representation of the ETC protein complexes and of the tricarboxylic acid (TCA) cycle (also known as the Krebs cycle or citric acid cycle) in the mitochondrial matrix.

Figure 4

(a) Reactions catalyzed by malate dehydrogenase (MDH), ATP-citrate synthase (ATP-CS), and aconitase, in the tricarboxylic acid (TCA) cycle (or Krebs cycle). The PDB codes of the structural models are 4WLF for MDH (human), 5UZQ [63] for ATP-CS (human) and 1C96 [64] for aconitase (Bos taurus). (b) Reaction catalyzed by creatine kinase U-type (Mia-CK). The PDB code of the structural model is 1QK1 [65].

Figure 5

Schematic representation of the oxidative stress effects generated by mitochondria.

Figure 6

(a) Structure of the voltage-dependent anion-selective channel protein 1 (VDAC1, salmon cartoon; the protein N-terminal domain, NTD, is highlighted in cyan). The main substances and ions, trafficking through the channel between the cytoplasm and the mitochondrial matrix, are schematically reported. The PDB code used for the structural model of human VDAC1 is 6G6U. (b) Reaction catalyzed by Mn-dependent superoxide dismutase (MnSOD). The PDB code used for the structural model of human MnSOD is 2ADQ [110].

Figure 7

Chemical structures of the therapeutic candidates targeting mitochoindrial ROS production (vitamins C and E, CoQ10, LA, and mitoQ) and ETC (mitoQ, J147, and metformin). The ETC complexes I-V are schematized in the figure, together with the mitochondrion.