Molecular Evolution of the Nuclear Factor (Erythroid-Derived 2)-Like 2 Gene Nrf2 in Old World Fruit Bats (Chiroptera: Pteropodidae)

Abstract

Mammals developed antioxidant systems to defend against oxidative damage in their daily life. Enzymatic antioxidants and low molecular weight antioxidants (LMWAs) constitute major parts of the antioxidant systems. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2, encoded by the Nrf2 gene) is a central transcriptional regulator, regulating transcription, of many antioxidant enzymes. Frugivorous bats eat large amounts of fruits that contain high levels of LMWAs such as vitamin C, thus, a reliance on LMWAs might greatly reduce the need for antioxidant enzymes in comparison to insectivorous bats. Therefore, it is possible that frugivorous bats have a reduced need for Nrf2 function due to their substantial intake of diet-antioxidants. To test whether the Nrf2 gene has undergone relaxed evolution in fruit-eating bats, we obtained Nrf2 sequences from 16 species of bats, including four Old World fruit bats (Pteropodidae) and one New World fruit bat (Phyllostomidae). Our molecular evolutionary analyses revealed changes in the selection pressure acting on Nrf2 gene and identified seven specific amino acid substitutions that occurred on the ancestral lineage leading to Old World fruit bats. Biochemical experiments were conducted to examine Nrf2 in Old World fruit bats and showed that the amount of catalase, which is regulated by Nrf2, was significantly lower in the brain, heart and liver of Old World fruit bats despite higher levels of Nrf2 protein in Old World fruit bats. Computational predictions suggest that three of these seven amino acid replacements might be deleterious to Nrf2 function. Therefore, the results suggest that Nrf2 gene might have experienced relaxed constraint in Old World fruit bats, however, we cannot rule out the possibility of positive selection. Our study provides the first data on the molecular adaptation of Nrf2 gene in frugivorous bats in compensation to the increased levels of LWMAs from their fruit-diet.

A metaanalysis of bat phylogenetics and positive selection based on genomes and transcriptomes from 18 species

“…Previously, work aimed at describing adaptive evolution in bats primarily focused on their unique traits, selecting families of genes to study for selection. These studies can broadly be divided into two categories, those that dealt with specific life traits, such as echolocation or metabolism related to frugivory (24, 64–73), and those that were related to pathogens or immunity (74–80). There are three studies that used larger datasets, two of which used whole-genome data (13, 23, 24).…”

High basal heat-shock protein expression in bats confers resistance to cellular heat/oxidative stress

“…As such, they have one of the greatest disparities between body mass and longevity (Ball et al 2018 ; Bozek et al 2017 ; Davies et al 2014 ; Hughes et al 2018 ; Munshi-South and Wilkinson 2010 ; Wilkinson and Adams 2019 ). Their longevity has been attributed, at least in part, to enhanced oxidative stress resistance and protein homeostasis (Salmon et al 2009 ; Yin et al 2016 ). The body temperature of bats raises drastically during flight (O'Shea et al 2014 ), and there is an excessive increase in metabolic rate and presumably oxidative stress, with heart rates up to 1200 bpm (O'Mara et al 2017 ; Podlutsky et al 2005 ).…”

A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases

“…Bats have also developed ingenious augmented immune response mechanisms enabling them to host viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebolavirus, without presenting signs of clinical disease [126]. Their protection against ageing and immune-mediated tissue damage may depend on robust anti-inflammatory defence mechanisms due to an up-regulation of the cytoprotective transcription factor NRF2 [127] reduction in inflammasome pathways via regulation of caspases [128] and DNA hypermethylation of age-and longevity-associated sites [129].…”