A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

Abstract

Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the age-related diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today. Keywords mitochondria; reactive oxygen species; human origins; diabetes; neurodegenerative diseases; aging; mtDNA: mitochondrial DNA; Mitochondrion (s), mitochondria (pl): cellular organelle of endosymbiotic origin that resides in the cytosol of most nucleated (eukaryotic) cells and which produces energy by oxidizing organic acids and fats with oxygen by the process oxidative phosphorylation (OXPHOS) and generates oxygen radicals (reactive oxygen species, ROS) as a toxic by-product; ROS: reactive oxygen species, oxygen radicals; OXPHOS: oxidative phosphorylation; Mitochondrial DNA (mtDNA): the portion of the mitochondrial genome that currently resides in the matrix of the mitochondrion, as a circular DNA molecule containing the mitochondrial rRNA genes, tRNA genes, and 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) enzyme complexes; CR: mtDNA control region; TCA: mitochondrial tricarboxylic acid cycle; SDH: succinate dehydrogenase; COX: cytochrome c oxidase, complex IV; ETC: mitochondrial electron transport chain, a part of the OXPHOS system; ANT: adenine nucleotide translocator; Unc 1,2,3: uncoupling proteins 1,2,3; Reactive oxygen species (ROS): primarily superoxide anion (O 2• − ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical ( • OH), commonly referred to as oxygen radicals; generated as a toxic by-product of oxidative energy production by OXPHOS damage the mitochondrial and cellular DNA, proteins, lipids, and other molecules causing oxidative stress; Oxidative phosphorylation (OXPHOS): the process by which the mitochondrion generates energy through oxidation of organic acids and fats with oxygen to create a capacitor [electron chemical gradient (ΔP = ΔΨ + ΔpH)] across the mito...

Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans

“…Mitochondrial functions are associated with aging in several ways, and the magnitude of these functions declines with age. Defects in mitochondrial homeostasis are closely linked to the development of human pathologies such as cancer, type 2 diabetes, and additional metabolic disorders (Wallace, 2005). While limited amounts of ROS appear to exert health‐promoting functions in diverse species (Ristow & Zarse, 2010), mitochondrial dysfunction and protein damage are mainly caused by excessive formation of ROS, which are by products of oxidative phosphorylation and energy production in the form of ATP (Tatsuta, 2009; Segref et al ., 2014).…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…Moreover, while fibrogenesis/fibrinolysis genes are predicted to be strong candidates to influence liver fibrosis, only one report has shown a link between transforming growth factor-β 1 (TGF-β 1) and angiotensinogen polymorphisms and obesity induced liver fibrosis [141]. Lastly, it should be mentioned that an association between naturally occurring variations in the mitochondrial genome and conditions of the cardiometabolic syndrome has been proposed [142,143]. Recently, Pravenec et al [142] using conplastic rat strains with the same nuclear genome but dissimilar mitochondrial genomes encoding oxidative phosphorylation proteins of differing amino acid composition showed differences in glucose and glycogen metabolism; two risk factors for type 2 diabetes.…”

Mitochondria and cancer: is there a morphological connection?

“…As a toxic by-product, OXPHOS generates reactive oxygen species (ROS). ROS can act both as tumour initiators, by inducing mutations in proto-oncogenes and tumour-supressors, and tumour promoters through enhancement of cell proliferation (reviewed in Behrend et al, 2003;Wallace, 2005). Impairment of the ETC very often results in excessive ROS production and subsequent oxidative stress.…”

“…Not only do they provide energy, but they also participate in numerous metabolic reactions and play central roles in apoptosis . Impairments of mitochondrial functions have been implicated in a wide variety of human pathologies, among which cancer and agerelated diseases (Wallace, 2005).…”