Interspecies Differences in Proteome Turnover Kinetics Are Correlated With Life Spans and Energetic Demands

Kyle Swovick,Denis Firsanov,Kevin A Welle,Jennifer R Hryhorenko,John P Wise,Craig George,Todd L Sformo,Andrei Seluanov,Vera Gorbunova,Sina Ghaemmaghami

doi:10.1074/mcp.ra120.002301

Abstract

AbstractCells continually degrade and replace damaged proteins. However, the high energetic demand of protein turnover generates reactive oxygen species that compromise the long-term health of the proteome. Thus, the relationship between aging, protein turnover, and energetic demand remains unclear. Here, we used a proteomic approach to measure rates of protein turnover within primary fibroblasts isolated from a number of species with diverse life spans including the longest-lived mammal, the bowhead whale. We show that organismal life span is negatively correlated with turnover rates of highly abundant proteins. In comparison with mice, cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production, and reduced reactive oxygen species levels. Despite having slower rates of protein turnover, naked mole rat cells tolerate protein misfolding stress more effectively than mouse cells. We suggest that in lieu of a rapid constitutive turnover, long-lived species may have evolved more energetically efficient mechanisms for selective detection and clearance of damaged proteins.

Highlights

Cross-species proteomic analyses show that turnover is correlated with life span. Correlation between life span and turnover is evident for abundant proteins. Long-lived naked mole rats have lower ATP production and reactive oxygen species (ROS) levels. Despite having slow turnover, naked mole rats tolerate protein misfolding stress
Conducting the analyses in quiescent cells allowed the measurement of turnover kinetics for stable proteins whose half-lives are significantly longer than the doubling time of the cells [23, 53, 54]
As a further illustration of this phenomenon, we showed that the turnover–life span slope (TLS) values of the 500 most abundant orthologous proteins within our data set were significantly lower than the 500 least abundant proteins (Fig. 3D)

Summary

Introduction

Cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production, and reduced reactive oxygen species levels. We focused these studies on comparisons of mouse and naked mole rat cells as these two rodent species differ widely in life spans and protein turnover rates yet are closely related evolutionarily and have similar body masses.

Results

Conclusion