Attention:The NSF Public Access Repository (PAR) system and access will be unavailable from 10:00 PM ET on Thursday, July 16 until 12:00 AM ET on Friday 17 due to maintenance. We apologize for the inconvenience.


Title: Does Cellular Metabolism from Primary Fibroblasts and Oxidative Stress in Blood Differ between Mammals and Birds? The (Lack-thereof) Scaling of Oxidative Stress
Abstract As part of mitonuclear communication, retrograde and anterograde signaling helps maintain homeostasis under basal conditions. Basal conditions, however, vary across phylogeny. At the cell-level, some mitonuclear retrograde responses can be quantified by measuring the constitutive components of oxidative stress, the balance between reactive oxygen species (ROS) and antioxidants. ROS are metabolic by-products produced by the mitochondria that can damage macromolecules by structurally altering proteins and inducing mutations in DNA, among other processes. To combat accumulating damage, organisms have evolved endogenous antioxidants and can consume exogenous antioxidants to sequester ROS before they cause cellular damage. ROS are also considered to be regulated through a retrograde signaling cascade from the mitochondria to the nucleus. These cellular pathways may have implications at the whole-animal level as well. For example, birds have higher basal metabolic rates, higher blood glucose concentration, and longer lifespans than similar sized mammals, however, the literature is divergent on whether oxidative stress is higher in birds compared with mammals. Herein, we collected literature values for whole-animal metabolism of birds and mammals. Then, we collected cellular metabolic rate data from primary fibroblast cells isolated from birds and mammals and we collected blood from a phylogenetically diverse group of birds and mammals housed at zoos and measured several parameters of oxidative stress. Additionally, we reviewed the literature on basal-level oxidative stress parameters between mammals and birds. We found that mass-specific metabolic rates were higher in birds compared with mammals. Our laboratory results suggest that cellular basal metabolism, total antioxidant capacity, circulating lipid damage, and catalase activity were significantly lower in birds compared with mammals. We found no body-size correlation on cellular metabolism or oxidative stress. We also found that most oxidative stress parameters significantly correlate with increasing age in mammals, but not in birds; and that correlations with reported maximum lifespans show different results compared with correlations with known aged birds. Our literature review revealed that basal levels of oxidative stress measurements for birds were rare, which made it difficult to draw conclusions.  more » « less
Award ID(s):
1656551
PAR ID:
10147086
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ;
Date Published:
Journal Name:
Integrative and Comparative Biology
Volume:
59
Issue:
4
ISSN:
1540-7063
Page Range / eLocation ID:
953 to 969
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Synopsis Birds that overwinter in temperate regions must be physiologically flexible to face the demands of living in a thermally fluctuating environment. Much of the previous literature on this topic focuses on whole-animal metabolic rates and corresponding cellular and molecular mechanisms that enable these birds to withstand the demands of changing environmental conditions. Basal and maximal shivering metabolic rates, as well as daily energy expenditure, typically increase in winter for small birds overwintering in cold climates, which might increase the production of reactive oxygen species (ROS) within mitochondria as a natural byproduct of aerobic metabolism. In this study, we measured summer to winter differences in oxidative balance in four species of resident passerine birds. Blood samples were taken from field-collected American goldfinch (Spinus tristis), black-capped chickadee (Poecile atricapillus), house finch (Haemorhous mexicanus), and house sparrow (Passer domesticus) during the summer and winter of 2023–2024 in South Dakota, USA. We determined plasma total antioxidant capacity and lipid oxidative damage, and red blood cell activities of three antioxidant enzymes: catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Lipid oxidative damage was significantly lower in winter for three of four species, and total antioxidant capacity for all species was significantly lower in winter compared with summer. Across all species, CAT activity was significantly higher in summer than in winter. In contrast, SOD activity was significantly higher in winter than in summer for all species. We also found species-level differences across the two seasons. These data suggest that the higher thermoregulatory costs in winter do not result in consistently elevated oxidative damage or antioxidant capacities relative to summer in small resident birds in cold climates, despite previously demonstrated winter increases in metabolic rates and energy expenditure. Such a result might occur as a function of either a reduction in dietary antioxidants and/or uncoupling of ROS production and metabolism in winter relative to summer or may be related to oxidative costs associated with reproduction. 
    more » « less
  2. ABSTRACT Oxidative stress occurs when there is an imbalance between oxidants and antioxidants, leading to the accumulation of reactive oxygen species (ROS). Excessive ROS can damage lipids, proteins, and DNA, contributing to cellular dysfunction and disease. Interestingly, premenopausal females tend to have lower levels of oxidative stress and higher concentrations of certain antioxidants, such as glutathione (GSH), compared to males and postmenopausal females. These differences point to the important role of sex hormones in regulating oxidative stress and its effects on the body. Yet, clinical and experimental studies report conflicting effects of estradiol, particularly across the menstrual cycle in premenopausal females and in estradiol supplementation in postmenopausal females. Here, we present a mechanistic mathematical model of hydrogen peroxide (H2O2), a key ROS, that explicitly incorporates estradiol and progesterone regulation of key enzymes. Using this model, we elucidate the mechanisms underlying females' lower oxidative stress and provide an explanation for the seemingly contradictory clinical observations at both steady state and during the menstrual cycle. We further apply the model to examine sex differences in cystathionine β‐synthase deficiency, explaining the attenuation of sex differences in key metabolites in the pathway. By connecting clinical observations with mathematical modeling, this work provides insights into the underlying mechanisms and paves the way for sex‐ and menopausal status‐specific approaches in medicine and drug development. 
    more » « less
  3. Santos, AL (Ed.)
    Peroxisomes are key regulators of cellular and metabolic homeostasis. These organelles play important roles in redox metabolism, the oxidation of very-long-chain fatty acids (VLCFAs), and the biosynthesis of ether phospholipids. Given the essential role of peroxisomes in cellular homeostasis, peroxisomal dysfunction has been linked to various pathological conditions, tissue functional decline, and aging. In the past few decades, a variety of cellular signaling and metabolic changes have been reported to be associated with defective peroxisomes, suggesting that many cellular processes and functions depend on peroxisomes. Peroxisomes communicate with other subcellular organelles, such as the nucleus, mitochondria, endoplasmic reticulum (ER), and lysosomes. These inter-organelle communications are highly linked to the key mechanisms by which cells surveil defective peroxisomes and mount adaptive responses to protect them from damages. In this review, we highlight the major cellular changes that accompany peroxisomal dysfunction and peroxisomal inter-organelle communication through membrane contact sites, metabolic signaling, and retrograde signaling. We also discuss the age-related decline of peroxisomal protein import and its role in animal aging and age-related diseases. Unlike other organelle stress response pathways, such as the unfolded protein response (UPR) in the ER and mitochondria, the cellular signaling pathways that mediate stress responses to malfunctioning peroxisomes have not been systematically studied and investigated. Here, we coin these signaling pathways as “peroxisomal stress response pathways”. Understanding peroxisomal stress response pathways and how peroxisomes communicate with other organelles are important and emerging areas of peroxisome research. 
    more » « less
  4. ABSTRACT The kidney filters nutrient waste and bodily fluids from the bloodstream, in addition to secondary functions of metabolism and hormone secretion, requiring an astonishing amount of energy to maintain its functions. In kidney cells, mitochondria produce adenosine triphosphate (ATP) and help maintain kidney function. Due to aging, the efficiency of kidney functions begins to decrease. Dysfunction in mitochondria and cristae, the inner folds of mitochondria, is a hallmark of aging. Therefore, age-related kidney function decline could be due to changes in mitochondrial ultrastructure, increased reactive oxygen species (ROS), and subsequent alterations in metabolism and lipid composition. We sought to understand if there is altered mitochondrial ultrastructure, as marked by 3D morphological changes, across time in tubular kidney cells. Serial block facing-scanning electron microscope (SBF-SEM) and manual segmentation using the Amira software were used to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented, compared to the 3-month, with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we show that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney due to aging. Disruption of the MICOS complex shows altered mitochondrial calcium uptake and calcium retention capacity, as well as generation of oxidative stress. We found significant, detrimental structural changes to aged kidney tubule mitochondria suggesting a potential mechanism underlying why kidney diseases occur more readily with age. We hypothesize that disruption in the MICOS complex further exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, thus impacting kidney health. Translational StatementDue to aging, the efficiency of kidney functions begins to decrease and the risk of kidney diseases may increase, but specific regulators of mitochondrial age-related changes are poorly explained. This study demonstrates the MICOS complex may be a target for mitigating age-related changes in mitochondria. The MICOS complex can be associated with oxidative stress and calcium dysregulation, which also arise in many kidney pathologies. Graphical AbstractKidney aging causes a decline in the MICOS complex, concomitant with metabolic, lipidomic, and mitochondrial structural alterations. 
    more » « less
  5. Mitochondria are hypothesized to display a biphasic response to reactive oxygen species (ROS) exposure. In this study, we evaluated the time course changes in mitochondrial performance and oxidative stress in house mice following X-irradiation. Forty-eight mice were equally divided among six groups, including a nonirradiated control and five experimental groups that varied in time between X-ray exposure and euthanasia (1 h and 1, 4, 7, and 10 days after X-irradiation). We measured parameters associated with mitochondrial respiratory function and ROS emission from isolated liver and skeletal muscle mitochondria and levels of oxidative damage and antioxidants in liver, skeletal muscle, and heart tissues. Mitochondrial function dropped initially after X-irradiation but recovered quickly and was elevated 10 days after the exposure. Hydrogen peroxide production, lipid peroxidation, and protein carbonylation showed inverse U-shaped curves, with levels returning to control or lower than control, 10 days after X-irradiation. Enzymatic antioxidants and markers for mitochondrial biogenesis exhibited a tissue-specific response after irradiation. These data provide the first chronological description of the mitohormetic response after a mild dose of irradiation and highlight the protective response that cells display to ROS exposure. This study also provides valuable information and application for future mitochondrial and oxidative stress studies in numerous physiological settings. 
    more » « less