Abstract
In several human diseases, such as cancer and neurodegenerative diseases, the levels of reactive oxygen species (ROS), produced mainly by mitochondrial oxidative phosphorylation, is increased. In cancer cells, the increase of ROS production has been associated with mtDNA mutations that, in turn, seem to be functional in the alterations of the bioenergetics and the biosynthetic state of cancer cells. Moreover, ROS overproduction can enhance the peroxidation of fatty acids in mitochondrial membranes. In particular, the peroxidation of mitochondrial phospholipid cardiolipin leads to the formation of reactive aldehydes, such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA), which are able to react with proteins and DNA. Covalent modifications of mitochondrial proteins by the products of lipid peroxidation (LPO) in the course of oxidative cell stress are involved in the mitochondrial dysfunctions observed in cancer and neurodegenerative diseases. Such modifications appear to affect negatively mitochondrial integrity and function, in particular energy metabolism, adenosine triphosphate (ATP) production, antioxidant defenses and stress responses. In neurodegenerative diseases, indirect confirmation for the pathogenetic relevance of LPO-dependent modifications of mitochondrial proteins comes from the disease phenotypes associated with their genetic alterations.
Highlights
It is noteworthy that cancer cells exhibit several metabolic alterations, which include increased fatty acid synthesis and glutamine metabolism, and dependence on aerobic glycolysis for energy needs [1,2], collectively referred to as the “Warburg effect” [3]
In an attempt to investigate further the possible impact of the oxidative modifications of mitochondrial proteins on the neuronal dysfunctions observed in neurodegenerative diseases, we provide here, in addition to an account of the adducts of lipid peroxidation (LPO) products with mitochondrial proteins so far identified and the related functional studies, whenever present in the literature (Table 4), a description of the mutations of the respective genes and the associated phenotypes, retrieved in the Online Mendelian Inheritance in
HNE adducts with ACO2 were detected in the hippocampus of patients with late-stage Alzheimer’s disease (AD) (LAD), in 185% excess over control brain samples; investigation of the functional consequences of the modification revealed that the enzymatic activity of ACO2 was reduced by 50%, supporting the view that oxidative modification determined functional impairment [121]
Summary
It is noteworthy that cancer cells exhibit several metabolic alterations, which include increased fatty acid synthesis and glutamine metabolism, and dependence on aerobic glycolysis for energy needs [1,2], collectively referred to as the “Warburg effect” [3]. Peroxidation of polyunsaturated fatty acids (PUFAs) generates an array of primary products, among which 4-hydroxynonenal (HNE) is one of the best-studied active lipid electrophiles. This aldehyde, by reacting with mitochondrial proteins, may contribute to altered mitochondrial functions in cancer cells, and in other diseases, in which oxidative stress is increased, such as chronic inflammations and neurodegenerative diseases [8,9]. Both ROS and reactive aldehydes can interact with mtDNA to produce mtDNA mutations and, as a consequence, alterations in encoded proteins that are crucial for mitochondrial functions [10,11,12]. We discuss the recent findings in mitochondrial dysfunctions in cancer cells related to fatty acid composition, ROS production, LPO, and the role played by mitochondrial lipoperoxidation products in cancer and neurodegenerative disorders
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