A mild impairment of mitochondrial electron transport has sex-specific effects on lifespan and aging in mice.

Bryan G Hughes,Siegfried Hekimi

doi:10.1371/journal.pone.0026116

Abstract

Impairments of various aspects of mitochondrial function have been associated with increased lifespan in various model organisms ranging from Caenorhabditis elegans to mice. For example, disruption of the function of the ‘Rieske’ iron-sulfur protein (RISP) of complex III of the mitochondrial electron transport chain can result in increased lifespan in the nematode worm C. elegans. However, the mechanisms by which impaired mitochondrial function affects aging remain under investigation, including whether or not they require decreased electron transport. We have generated knock-in mice with a loss-of-function Risp mutation that is homozygous lethal. However, heterozygotes (Risp+/P224S) were viable and had decreased levels of RISP protein and complex III enzymatic activity. This decrease was sufficient to impair mitochondrial respiration and to decrease overall metabolic rate in males, but not females. These defects did not appear to exert an overtly deleterious effect on the health of the mutants, since young Risp+/P224S mice are outwardly normal, with unaffected performance and fertility. Furthermore, biomarkers of oxidative stress were unaffected in both young and aged animals. Despite this, the average lifespan of male Risp+/P224S mice was shortened and aged Risp+/P224S males showed signs of more rapidly deteriorating health. In spite of these differences, analysis of Gompertz mortality parameters showed that Risp heterozygosity decreased the rate of increase of mortality with age and increased the intrinsic vulnerability to death in both sexes. However, the intrinsic vulnerability was increased more dramatically in males, which resulted in their shortened lifespan. For females, the slower acceleration of age-dependent mortality results in significantly increased survival of Risp+/P224S mice in the second half of lifespan. These results demonstrate that even relatively small perturbations of the mitochondrial electron transport chain can have significant physiological effects in mammals, and that the severity of those effects can be sex-dependent.

Highlights

Mitochondrial oxidative phosphorylation is essential to aerobic organisms, as it provides the bulk of usable energy in the form of ATP
We used the techniques of homologous recombination in embryonic stem cells and Flp/Flp recombinase recognition target (FRT) site-specific recombination to generate a line of mice carrying a Risp mutation identical to that found to increase lifespan in C. elegans
A small loss of activity of complex III is sufficient to alter mitochondrial function Several studies have used pharmaceutical inhibitors to show that inhibition of greater than 40–80 percent of complex III activity is required to substantially compromise respiratory function of mitochondria from various tissues [42,43,44,45]. This would imply that a complex III enzymatic deficiency of between 15 and 21 percent, as we observed in Risp+/P224S mice, should not affect mitochondrial function or produce in vivo effects

Summary

Introduction

Mitochondrial oxidative phosphorylation is essential to aerobic organisms, as it provides the bulk of usable energy in the form of ATP. Mitochondrial defects are often studied in the context of severe deficits in function, resulting in serious negative health consequences These mitochondrial diseases can be caused by mutations to a wide variety of mitochondrial and nuclearencoded genes [1,2]. Impairments of mitochondrial function have been found to accompany numerous age-dependent diseases, such as atherosclerosis, type 2 diabetes and various neurodegenerative disorders [3,4,5], as well as aging in general, even in the absence of overt disease This has led to a widespread belief that mitochondrial dysfunction plays a causative role in aging [6]. RNA interference (RNAi) against various components of mitochondria, including respiratory chain subunits, have been shown to extend lifespan [11,12,13,14], albeit by a mechanism that appears to be different from that triggered by the mutations [11]

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Conclusion