Comparative studies of mitochondrial reactive oxygen species in animal longevity: Technical pitfalls and possibilities

Munro, Daniel; Pamenter, Matthew E.

doi:10.1111/acel.13009

Cited by 28 publications

(24 citation statements)

References 96 publications

(159 reference statements)

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“…Under these conditions, mitochondria and NOX are the major ROS producers ( Tarafdar and Pula, 2018 ; Barua et al, 2019 ). However, before its diffusion to the cytoplasm, the internal consumption of H 2 O 2 in mitochondria is much higher than originally anticipated ( Munro and Pamenter, 2019 ) and during oxidative stress, mitochondria may be victims rather than producers of oxidative damage ( Gandhi and Abramov, 2012 ). Indeed, in AD models, the effects of mitochondrial ROS were found to be much smaller compared with those of NOX-produced ROS ( Angelova and Abramov, 2018 ).…”

Section: The Cytoplasmic Antioxidant Systemmentioning

confidence: 99%

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

Zilberter

Zilberter²

2020

eNeuro

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The ketogenic diet (KD) has been successfully used for a century for treating refractory epilepsy and is currently seen as one of the few viable approaches to the treatment of a plethora of metabolic and neurodegenerative diseases. Empirical evidence notwithstanding, there is still no universal understanding of KD mechanism(s). An important fact is that the brain is capable of using ketone bodies for fuel. Another critical point is that glucose’s functions span beyond its role as an energy substrate, and in most of these functions, glucose is irreplaceable. By acting as a supplementary fuel, ketone bodies may free up glucose for its other crucial and exclusive function. We propose that this glucose-sparing effect of ketone bodies may underlie the effectiveness of KD in epilepsy and major neurodegenerative diseases, which are all characterized by brain glucose hypometabolism.

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“…Conversely, naked mole-rats are largely non-responsive to hypercapnia and associated acidity-related pain responses are largely absent [49,50]. Naked mole-rats also have numerous adaptations that are not as obviously linked to their natural habitat, including a remarkable resistance to cancer [51,52], they are the only mammalian thermo-conformer and almost entirely ectothermic for regulation of body temperature [53,54] and they have remarkable longevity [55,56,57,58]. These traits make the naked mole-rat an important animal model for a range of human diseases and for furthering understanding of pathways underlying cancer resistance and longevity [59,60,61].…”

Section: Introductionmentioning

confidence: 99%

Post-Translational Deimination of Immunological and Metabolic Protein Markers in Plasma and Extracellular Vesicles of Naked Mole-Rat (Heterocephalus glaber)

Pamenter

Uysal-Onganer

Huynh

et al. 2019

IJMS

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Naked mole-rats are long-lived animals that show unusual resistance to hypoxia, cancer and ageing. Protein deimination is an irreversible post-translational modification caused by the peptidylarginine deiminase (PAD) family of enzymes, which convert arginine into citrulline in target proteins. Protein deimination can cause structural and functional protein changes, facilitating protein moonlighting, but also leading to neo-epitope generation and effects on gene regulation. Furthermore, PADs have been found to regulate cellular release of extracellular vesicles (EVs), which are lipid-vesicles released from cells as part of cellular communication. EVs carry protein and genetic cargo and are indicative biomarkers that can be isolated from most body fluids. This study was aimed at profiling deiminated proteins in plasma and EVs of naked mole-rat. Key immune and metabolic proteins were identified to be post-translationally deiminated, with 65 proteins specific for plasma, while 42 proteins were identified to be deiminated in EVs only. Using protein-protein interaction network analysis, deiminated plasma proteins were found to belong to KEEG (Kyoto Encyclopedia of Genes and Genomes) pathways of immunity, infection, cholesterol and drug metabolism, while deiminated proteins in EVs were also linked to KEEG pathways of HIF-1 signalling and glycolysis. The mole-rat EV profiles showed a poly-dispersed population of 50–300 nm, similar to observations of human plasma. Furthermore, the EVs were assessed for three key microRNAs involved in cancer, inflammation and hypoxia. The identification of post-translational deimination of critical immunological and metabolic markers contributes to the current understanding of protein moonlighting functions, via post-translational changes, in the longevity and cancer resistance of naked mole-rats.

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“…However, both the activity (Page et al 2010) and the amount (Brown and Stuart 2007) of the mitochondrial form of superoxide dismutase, MnSOD, positively correlated with mammalian longevity, similarly to what we report in the current study for mtBER. Other studies also point to an especially important role of mitochondrial compared to total cell tissue antioxidants concerning longevity (Schriner et al 2005;Munro and Baldy 2019;Munro and Pamenter 2019).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial base excision repair positively correlates with longevity in the liver and heart of mammals

et al. 2020

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Damage to DNA is especially important for aging. High DNA repair could contribute, in principle, to lower such damage in long-lived species. However, previous studies showed that repair of endogenous damage to nuclear DNA (base excision repair, BER) is negatively or not correlated with mammalian longevity. However, we hypothesize here that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus measured activities and/or protein levels of various BER enzymes including DNA glycosylases, NTHL1 and NEIL2, and the APE endonuclease both in total and mitochondrial liver and heart fractions from up to eight mammalian species differing by 13-fold in longevity. Our results show, for the first time, a positive correlation between (mitochondrial) BER and mammalian longevity. This suggests that the low steady-state oxidative damage in mitochondrial DNA of long-lived species would be due to both their lower mitochondrial ROS generation and their higher mitochondrial BER. Long-lived mammals do not need to continuously maintain high nuclear BER levels because they release less mitROS to the cytosol. This can be the reason why they tend to show lower nuclear BER values. The higher mitochondrial BER of long-lived mammals contributes to their superior longevity, agrees with the updated version of the mitochondrial free radical theory of aging, and indicates the special relevance of mitochondria and mitROS for aging. Keywords Mitochondria. DNA repair. AP endonuclease. DNA glycosylases. Aging Abbreviations APE1 Apurinic/apyrimidinic endonuclease BER Base excision repair DR Dietary restriction mtDNA Mitochondrial DNA nDNA Nuclear DNA NTHL1 Endonuclease III homolog 1 NEIL2 Nei-like 2 5OHC 5-Hydroxycytosine

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“…Ecologists and evolutionary biologists have long been intrigued by inter‐ and intraspecific variation in life‐history strategies and the trade‐offs that arise from the interactions among life‐history traits (Stearns, 1992; Zera & Harshman, 2001). Considerable effort has been spent attempting to elucidate the physiological mechanisms that underlie individual variation in life‐history traits such as physical performance (Irschick & Higham, 2016; Killen, Calsbeek, & Williams, 2017; Scott, Guo, & Dawson, 2018), longevity (Miller et al ., 2011; Munro & Pamenter, 2019), reproduction (Harshman & Zera, 2007; Williams, 2012 a ; Zhang & Hood, 2016), and growth and development (Mueller et al ., 2015). Recently, researchers have focused on bioenergetics and oxidative stress (Monaghan, Metcalfe, & Torres, 2009; Zhang & Hood, 2016; Munro & Pamenter, 2019), as well as hormonal regulation (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Considerable effort has been spent attempting to elucidate the physiological mechanisms that underlie individual variation in life‐history traits such as physical performance (Irschick & Higham, 2016; Killen, Calsbeek, & Williams, 2017; Scott, Guo, & Dawson, 2018), longevity (Miller et al ., 2011; Munro & Pamenter, 2019), reproduction (Harshman & Zera, 2007; Williams, 2012 a ; Zhang & Hood, 2016), and growth and development (Mueller et al ., 2015). Recently, researchers have focused on bioenergetics and oxidative stress (Monaghan, Metcalfe, & Torres, 2009; Zhang & Hood, 2016; Munro & Pamenter, 2019), as well as hormonal regulation (e.g. sex steroids, glucocorticoids) (Crespi et al ., 2013; Vera, Zenuto, & Antenucci, 2017; Eyck et al ., 2019), as potential physiological mechanisms mediating life‐history trade‐offs.…”

Section: Introductionmentioning

confidence: 99%

Evaluating endoplasmic reticulum stress and unfolded protein response through the lens of ecology and evolution

et al. 2020

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Considerable progress has been made in understanding the physiological basis for variation in the life‐history patterns of animals, particularly with regard to the roles of oxidative stress and hormonal regulation. However, an underappreciated and understudied area that could play a role in mediating inter‐ and intraspecific variation of life history is endoplasmic reticulum (ER) stress, and the resulting unfolded protein response (UPRER). ER stress response and the UPRER maintain proteostasis in cells by reducing the intracellular load of secretory proteins and enhancing protein folding capacity or initiating apoptosis in cells that cannot recover. Proper modulation of the ER stress response and execution of the UPRER allow animals to respond to intracellular and extracellular stressors and adapt to constantly changing environments. ER stress responses are heritable and there is considerable individual variation in UPRER phenotype in animals, suggesting that ER stress and UPRER phenotype can be subjected to natural selection. The variation in UPRER phenotype presumably reflects the way animals respond to ER stress and environmental challenges. Most of what we know about ER stress and the UPRER in animals has either come from biomedical studies using cell culture or from experiments involving conventional laboratory or agriculturally important models that exhibit limited genetic diversity. Furthermore, these studies involve the assessment of experimentally induced qualitative changes in gene expression as opposed to the quantitative variations that occur in naturally existing populations. Almost all of these studies were conducted in controlled settings that are often quite different from the conditions animals experience in nature. Herein, we review studies that investigated ER stress and the UPRER in relation to key life‐history traits including growth and development, reproduction, bioenergetics and physical performance, and ageing and senescence. We then ask if these studies can inform us about the role of ER stress and the UPRER in mediating the aforementioned life‐history traits in free‐living animals. We propose that there is a need to conduct experiments pertaining to ER stress and the UPRER in ecologically relevant settings, to characterize variation in ER stress and the UPRER in free‐living animals, and to relate the observed variation to key life‐history traits. We urge others to integrate multiple physiological systems and investigate how interactions between ER stress and oxidative stress shape life‐history trade‐offs in free‐living animals.

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Comparative studies of mitochondrial reactive oxygen species in animal longevity: Technical pitfalls and possibilities

Cited by 28 publications

References 96 publications

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

Post-Translational Deimination of Immunological and Metabolic Protein Markers in Plasma and Extracellular Vesicles of Naked Mole-Rat (Heterocephalus glaber)

Mitochondrial base excision repair positively correlates with longevity in the liver and heart of mammals

Evaluating endoplasmic reticulum stress and unfolded protein response through the lens of ecology and evolution

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