Abstract
Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation. Although excess ROS reduces lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived. We address this paradox by identifying the constitutive activation of the NRF2 master antioxidant response in Neoaves (~95% of bird species), providing an adaptive mechanism capable of counterbalancing high ROS levels. We demonstrate that a KEAP1 mutation in the Neoavian ancestor disrupted the repression of NRF2 by KEAP1, leading to constitutive NRF2 activity and decreased oxidative stress in wild Neoaves tissues and cells. Our evidence suggests this ancient mutation induced a compensatory program in NRF2-target genes with functions beyond redox regulation—including feather development—while enabling significant metabolic rate increases that avoid trade-offs with lifespan. The strategy of NRF2 activation sought by intense clinical investigation therefore appears to have also unlocked a massively successful evolutionary trajectory.
Highlights
Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation
Consistent with this, within a longrange annotated genome assembly for the band-tailed pigeon (Patagioenas fasciata), we found a KEAP1 coding sequence fused at the 3′ end to the adjacent ILF3 reading frame, conjoined precisely at the conserved KEAP1 exon boundary and predicted recombination breakpoints we detected (R442, Human KEAP1 numbering; Fig. 1c); the noncontiguous remainder of the KEAP1 3′ end was inverted to the antisense strand
We demonstrated that the loss of NRF2 repression by KEAP1 in Neoaves has resulted in increased cellular resistance to oxidative stress burden, which may potentially form an adaptive mechanism capable of counterbalancing high levels of ROS in Neoavian tissues
Summary
Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation. Excess ROS reduces lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived We address this paradox by identifying the constitutive activation of the NRF2 master antioxidant response in Neoaves (~95% of bird species), providing an adaptive mechanism capable of counterbalancing high ROS levels. Oxidative stress is a major constraint on animal performance[13,14,15,16], yet the role of ROS in shaping the evolution of birds has often been overlooked This is striking, since birds display a stunning diversity of flight modes[5], small body sizes[17], and clutch and egg sizes[18,19], all of which may be expected to further disrupt avian redox balance[7,8,13,14,16,20]. We demonstrate that a KEAP1 mutation in the Neoavian ancestor disrupted the highly conserved binding and repression of NRF2 by KEAP1, leading to constitutive NRF2 activity, increased
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