Mitochondrial Dysfunction in Cancer and Neurodegenerative Diseases: Spotlight on Fatty Acid Oxidation and Lipoperoxidation Products

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.

Mitotherapy for Fatty Liver by Intravenous Administration of Exogenous Mitochondria in Male Mice

“…Excessive ROS enhance the peroxidation of fatty acids in mitochondrial membranes to produce lipid peroxidation productions, such as MDA (Barrera et al, 2016). In fatty liver mice, MDA remarkably increased, which indicated that the cells were damaged by overproduction of ROS.…”

Anti-oxidant and Anti-microbial Activities of Herb-combined Remedies used in Traditional Korean Medicine for Treating Breast Cancer

“…하지만 과도하게 발생된 ROS는 산화적 스트레스를 유발하여 유전자 돌연변이 유발과, 체내 세포와 조직에 비가역적인 손상 및 각 종 암의 발생뿐 만 아니라 치매와 같은 퇴행성 신경 질환의 주요한 원인이 되고 [3,16,22], 면역 질환 [19,38], 당뇨병 [31] 및 노화 [17] [8], 해독 [32], 해열 [1], 방부 [6], 항염증 [40] Sipyukmiyuki-eum; 2) Danjacheongpi-tang; 3) Jipae-san Ⅰ; Table 2에 Values are presented as the mean ± SD. 1) Hot water extracts of Sipyukmiyuki-eum; 2) Hot water extracts of Danjacheongpi-tang; 3) Hot water extracts of Jipae-san Ⅰ;…”

Mitochondrial Dysfunction and Oxidative Stress in Pediatric Diseases

“…5,87 In cancer cells, the increased ROS production is linked to mtDNA mutations and to alterations of their bioenergetics and biosynthetic state. 88 Several metabolic alterations are found in cancer cells, such as increased fatty acid synthesis and glutamine metabolism and increased aerobic glycolysis, known as the "Warburg effect," which is thought to be caused by defective mitochondria: the aerobic glycolysis enables cancer cells to use glucose for the biosynthesis of macromolecules, thus supporting their rapid growth. Other mechanisms of damage include the peroxidation of fatty acids in mitochondrial membranes, with the production of reactive aldehydes, which react with DNA and proteins.…”

“…Other mechanisms of damage include the peroxidation of fatty acids in mitochondrial membranes, with the production of reactive aldehydes, which react with DNA and proteins. [88][89][90][91] A mitochondrial dysfunction is a hallmark in several genetic diseases characterized by high neoplastic risk starting from pediatric age 92 : these syndromes represent a valid model to study the correlation between mitochondrial impairment and tumor development. Among these diseases, one of the best known is Ataxia-Telangiectasia (AT), an autosomal recessive disorder caused by mutational inactivation of ATM gene.…”