CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution

Qinchuan Wang,Martin F Schneider,Kevin R Murphy,An-Chi Wei,David Mohr,M.a Bianchet ,C Danh ,Jonathan Granger ,Anthony Cammarato,Mark N Wu,Peisong Gao,Corina Antonescu ,Liliana Florea ,Naili Liu,Gabe S Bever ,Richard M Lovering,Erick O Hernández‐Ochoa ,Sergi Regot,C Conover Talbot,Susan Aja,Meera Viswanathan ,Kathryn R Wagner,Ian D Blum,Mark E Anderson

doi:10.1038/s41467-021-23549-3

Abstract

Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca2+ and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.

Highlights

Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life
Given that the detrimental roles of ox-calmodulin-dependent protein kinase II (CaMKII) are apparently tolerated by natural selection in humans and mice, we hypothesized that ox-CaMKII is a critically important, but heretofore unrecognized, molecular example of antagonistic pleiotropy, and predicted that ox-CaMKII would contribute to beneficial roles favorable to natural selection
Predating the MM/CM by about 400 million years, T287 appeared on the same branch as CaMKII itself, while the serine 280 (S280) pathway evolved slightly later, and both residues are conserved since their first appearance (Fig. 1b)

Summary

Introduction

Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. The power of natural selection to either promote beneficial or remove detrimental effects from a population/lineage is thought to wane as the realization of those effects moves increasingly late in life Evolution within this “selection shadow” is predicted to take on a more stochastic pattern with the unfortunate consequence that deleterious, aging-related mutations can accumulate with relative freedom[4]. Antagonistic pleiotropy helps complete this theoretical structure by predicting that the genetic traits responsible for some or all aging-related diseases—and even aging itself—are maintained because at some level they are being actively promoted by positive selection. Given that the detrimental roles of ox-CaMKII are apparently tolerated by natural selection in humans and mice, we hypothesized that ox-CaMKII is a critically important, but heretofore unrecognized, molecular example of antagonistic pleiotropy, and predicted that ox-CaMKII would contribute to beneficial roles favorable to natural selection

Methods

Results

Conclusion