The SFT-1 and OXA-1 respiratory chain complex assembly factors influence lifespan by distinct mechanisms in C. elegans

Sara Maxwell,Carol Delaney,Charles Brabin,Alison Woollard,Garry Brown,Peter J Appleford,Ruth Brown,Joanne Harding

doi:10.1186/2046-2395-2-9

Abstract

BackgroundC. elegans mitochondrial (Mit) mutants have disrupted mitochondrial electron transport chain function, yet, surprisingly, they are often long-lived, a property that has offered unique insights into the molecular mechanisms of aging. In this study, we examine the phenotypic consequences of reducing the expression of the respiratory chain complex assembly factors sft-1 (homologous to human SURF1) and oxa-1 (homologous to human OXA1) by RNA interference (RNAi). Mutations in human SURF1 are associated with Leigh syndrome, a neurodegenerative condition of the brain caused by cytochrome oxidase (COX) deficiency. Both SURF1 and OXA1 are integral proteins of the inner mitochondrial membrane, functioning in the COX assembly pathway.ResultsRNAi of both of these genes in C. elegans is associated with increased longevity, but the mechanism by which lifespan is extended is different in each case. sft-1(RNAi) animals display lifespan extension that is dependent on the daf-16 insulin-like signaling pathway, and associated with sensitivity to oxidative stress. oxa-1(RNAi) animals, in contrast, exhibit increased longevity that is at least partially independent of daf-16, and associated with a reduced developmental rate and increased resistance to oxidative stress.ConclusionsThis study further delineates the consequences of mitochondrial dysfunction within a whole organism that will ultimately help provide new models for human mitochondrial-associated diseases. The difference in phenotype observed upon down-regulation of these two COX assembly factors, as well as phenotypic differences between these factors and other respiratory chain components analyzed thus far, illustrates the complex inter-relationships that exist among energy metabolism, reproduction and aging even in this simplest of metazoan model organisms.

Highlights

C. elegans mitochondrial (Mit) mutants have disrupted mitochondrial electron transport chain function, yet, surprisingly, they are often long-lived, a property that has offered unique insights into the molecular mechanisms of aging
RNA interference (RNAi) of sft-1 or oxa-1 leads to significantly reduced gene expression and consequent reduction in cytochrome oxidase activity as assayed in whole animals in the case of sft-1 RNAi (Figure 1A,B)
Knockdown of either gene was associated with decreased brood size (a 27% decrease, on average, following sft-1 RNAi by injection, and a 57% decrease, on average, in worms injected with oxa-1 dsRNA, Figure 1C)

Summary

Introduction

C. elegans mitochondrial (Mit) mutants have disrupted mitochondrial electron transport chain function, yet, surprisingly, they are often long-lived, a property that has offered unique insights into the molecular mechanisms of aging. There are a number of reports of the consequences of defects in mitochondrial function in C. elegans These studies were often undertaken in the first instance to evaluate C. elegans as a potential model system for the investigation of pathogenic mechanisms in human mitochondrial disease; some unexpected phenotypic consequences of mitochondrial enzyme deficiencies were soon identified, in relation to lifespan. While these are not immediately relevant to the human diseases, they may provide unique insights into the molecular mechanisms of aging [8,9]

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