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Multiple Roles of Mitochondria in Aging Processes Physiol. Res. 65 (Suppl. 5): S519-S531, 2016 https://doi.org/10.33549/physiolres.933538 REVIEW Multiple Roles of Mitochondria in Aging Processes M. CEDIKOVA1,2, P. PITULE2,3, M. KRIPNEROVA4, M. MARKOVA1, J. KUNCOVA1,2 1Department of Physiology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic, 2Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic, 3Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic, 4Department of Biology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic Received March 27, 2016 Accepted October 26, 2016 Summary is defined as an age-dependent or age-progressive decline Aging is a multifactorial process influenced by genetic factors, in the intrinsic physiological function, leading to nutrition, and lifestyle. According to mitochondrial theory of an increase in age-specific mortality rate and a decrease aging, mitochondrial dysfunction is widely considered a major in age-specific reproductive rate (Anton et al. 2015, contributor to age-related processes. Mitochondria are both the Basaria 2013, Fulop et al. 2010). Human aging starts main source and targets of detrimental reactions initiated in after the third decade and is commonly associated with association with age-dependent deterioration of the cellular the accumulation of physical, psychological, and social functions. Reactions leading to increased reactive oxygen species changes leading to general decline in wellness, reduction generation, mtDNA mutations, and oxidation of mitochondrial in mobility (which is critical factor impacting the quality proteins result in subsequent induction of apoptotic events, of life) and the onset of many age-related diseases impaired oxidative phosphorylation capacity, mitochondrial including atherosclerosis, heart disease, hypertension, dynamics, biogenesis and autophagy. This review summarizes cancer, arthritis, cataract, Alzheimer's disease, and type 2 the major changes of mitochondria related to aging, with diabetes mellitus (Baumgartner et al. 1998, Liu 2014). In emphasis on mitochondrial DNA mutations, the role of the spite of intense research, the mechanisms that underlie reactive oxygen species, and structural and functional changes of age-dependent changes are still largely unknown (Barja mitochondria. 2013). Mitochondrial dysfunction has long been Key words considered a major contributor to aging and age-related Mitochondria • Aging • mtDNA • Oxidative stress diseases (for a review, see Chistiakov et al. 2014). With advanced age, mitochondrial dynamics, biogenesis, and Corresponding author oxidative phosphorylation capacity decrease, whereas J. Kuncová, Department of Physiology, Biomedical Center, Faculty mitochondrial DNA (mtDNA) damage, production of of Medicine in Pilsen, Charles University, Alej Svobody 76, reactive oxygen species (ROS), induction of apoptotic 323 00 Plzeň, Czech Republic. E-mail: [email protected] events, and oxidation of numerous mitochondrial proteins leading to formation of protein-protein cross-linkages and Introduction protein fragmentation progressively increase (reviewed in Chistiakov et al. 2014, Gonzalez-Freire et al. 2015). Progressive aging of the elderly population is Accumulation of ROS and oxidative damage have an increasingly important feature of societies in the been linked to multiple pathologies, including developed countries (Olshansky 2013). In biology, aging neurodegenerative diseases, diabetes, cancer, and PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) 2016 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres S520 Cedikova et al. Vol. 65 premature aging. In 1956, Harman postulated free radical machinery enabling many distinct metabolic processes theory of aging stating that aging process depends on (Wang et al. 2010). They are found in almost all human ROS production leading to oxidative damage and cells with exception of mature erythrocytes (Logan 2006, subsequent malfunction of nucleic acids, proteins and Zhang et al. 2012). lipids (Harman 1956). This theory was later extended to The primary function of mitochondria is to mitochondrial theory of aging suggesting that both the produce adenosine triphosphate (ATP) by the process of main source and target of oxygen and nitrogen radicals oxidative phosphorylation through the respiratory system produced in association with aging processes are (they synthesize more than 95 % ATP for cellular mitochondria (Payne and Chinnery 2015, Ziegler et al. utilization). General view of the mitochondrial respiratory 2015). Dysfunction of mitochondrial electron- system is shown in Figure 1A. This system is composed transporting system leads to increased production of of four respiratory complexes (I-IV) localized in the inner ROS, which results in mtDNA damage followed by mitochondrial membrane, two mobile carriers (coenzyme mutations causing compromised mitochondrial protein Q and cytochrome c), and ATP synthase. On complexes I function and further increase in production of oxygen and and II, reduced coenzymes, nicotinamide adenine nitrogen radicals. Although this theory was challenged by dinucleotide (NADH) and flavin adenine dinucleotide some experimental observations documenting that at least (FADH2) are oxidized, respectively. Reduced coenzymes in some species, reduced oxidative damage may not are generated by various dehydrogenases particularly in invariably prolong life span, excessive production of tricarboxylic acid cycle. The electrons released by the ROS related to mitochondrial malfunction is still oxidation of reduced coenzymes are transferred through considered an important factor contributing to accelerated the respiratory complexes to the molecular oxygen aging process (Avantaggiato et al. 2015, López-Lluch et providing energy to pump protons across the inner al. 2015). In addition, mitochondrial health and aging mitochondrial membrane (complexes I, III and IV). may be affected by subject parameters like physical Created electrochemical potential (proton-motive force) activity history (Barrientos et al. 1996, Gnaiger 2009, is then used by ATP synthase to form ATP from ADP Lanza et al. 2008), age (Bua et al. 2006), caloric and Pi (Benard et al. 2006, Zeviani and Di Donato 2004). restriction (Schiff et al. 2011), drugs (Heller et al. 2012), In addition to energy, mitochondria also generate and various comorbidities including obesity (Boudina ROS and represent the major source of their cellular and Graham 2014), sarcopenia (Figueiredo et al. production. Leakage of electrons, mainly from complexes 2008, Marzetti et al. 2010, Moore et al. 2010), I and III, leads to one-electron reduction of oxygen to hypertriglyceridemia, dyslipoproteinemia, insulin form superoxide anion that is the precursor of most ROS resistance, abnormal glucose tolerance, and hypertension and a mediator in oxidative chain reactions. Superoxide (Bonomini et al. 2015). anion then undergoes dismutation catalyzed by In this review, we briefly revise the major superoxide dismutase thus producing longer-lived and changes of mitochondria related to aging, with emphasis membrane permeant hydrogen peroxide. This molecule on: i) structural and functional changes of mitochondria, can be fully or partially reduced to water or hydroxyl ii) mitochondrial DNA mutations, and iii) the role of radical, respectively (Turrens 2003, Murphy 2009). ROS. Under normal conditions, ROS are maintained at physiological levels by several endogenous systems of Overview of mitochondria – structure and antioxidant enzymes, such as superoxide dismutase functions (SOD), catalase, glutathione peroxidases and glutathione reductase (Dai et al. 2014). Schematic view of ROS About 1.5 billion years ago, mitochondria (from production is shown in Figure 2. Greek mitos (thread-like) and khondros (grain or Besides this, mitochondria also play an essential granule)) and eukaryotic cells established a symbiotic role in amino acid and lipid metabolism, calcium relationship. Mitochondria are subcellular, self- homeostasis, regulation of apoptosis, cell cycle autonomous, highly dynamic and pleomorphic organelles regulation, and thermogenesis (Friedman and Nunnari surrounded by double-membrane system. They contain 2014). their own genetic system and sophisticated enzymatic 2016 Mitochondria and Aging S521 Fig. 1. General view of the mitochondrial respiratory system and genome. A. The respiratory system consists of four complexes (I – NADH dehydrogenase, II – succinate dehydrogenase, III – cytochrome c reductase and VI – cytochrome c oxidase) and ATP synthase. Subunits of complexes encoded by mtDNA are shown in same colors as in part B. CoQ – coenzyme Q, CytC – cytochrome c, e– – electron. B. mtDNA is schematized together with the encoded genes. The D-loop contains the promoters for transcription of the H and L strand (HSP, LSP) as well as the origin of replication of the leading strand of mtDNA (OH). The color indicates to which part of the respiratory system the subunit-encoding gene belongs to. S522 Cedikova et al. Vol. 65 Fig. 2. Schematic representation of ROS production. In the course of metabolic processes are generated reactive oxygen and nitrogen species and this scheme shows the process of their transformation. – •– e – electron, O2 – oxygen, O2 – superoxide – anion, H2O2 – hydrogen peroxide, OH –
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