Succinate Dehydrogenase Upregulation Destabilize Complex I and Limits the Lifespan of gas-1 Mutant

Claire Pujol,Linda Baumann,Marija Sumakovic,Victor Pavlenko,Ivana Bratic-Hench,Jürgen Hench,Arnaud Mourier,Aleksandra Trifunovic,Nagendra Yadava

doi:10.1371/journal.pone.0059493

Abstract

Many Caenorhabditis elegans mutants with dysfunctional mitochondrial electron transport chain are surprisingly long lived. Both short-lived (gas-1(fc21)) and long-lived (nuo-6(qm200)) mutants of mitochondrial complex I have been identified. However, it is not clear what are the pathways determining the difference in longevity. We show that even in a short-lived gas-1(fc21) mutant, many longevity assurance pathways, shown to be important for lifespan prolongation in long-lived mutants, are active. Beside similar dependence on alternative metabolic pathways, short-lived gas-1(fc21) mutants and long-lived nuo-6(qm200) mutants also activate hypoxia-inducible factor –1α (HIF-1α) stress pathway and mitochondrial unfolded protein response (UPRmt). The major difference that we detected between mutants of different longevity, is in the massive loss of complex I accompanied by upregulation of complex II levels, only in short-lived, gas-1(fc21) mutant. We show that high levels of complex II negatively regulate longevity in gas-1(fc21) mutant by decreasing the stability of complex I. Furthermore, our results demonstrate that increase in complex I stability, improves mitochondrial function and decreases mitochondrial stress, putting it inside a “window” of mitochondrial dysfunction that allows lifespan prolongation.

Highlights

Mitochondria are organelles found in almost every eukaryotic cell
Our results show that mitochondrial dysfunction, even in a shortlived mutant like gas-1(fc21), activates longevity assurance program that include alternative metabolic and stress pathways
These pathways on their own cannot ensure lifespan prolongation that seems to be dependent on the level and type of mitochondrial dysfunction

Summary

Introduction

Mitochondria are organelles found in almost every eukaryotic cell. They produce a bulk of cellular energy in the form of ATP, which is required for numerous processes in the cell. Majority of ATP is formed during oxidative phosphorylation (OXPHOS) through the mitochondrial respiratory chain (MRC), a series of large enzyme complexes that couples the transfer of electrons to the creation of a proton gradient across the inner mitochondrial membrane. Mutations in CO I subunits encoded by either mitochondrial (mtDNA) or nuclear DNA cause infantile encephalomyopathies or multisystem disorders in adults. Clinical symptoms in these patients may vary from mild to fatal [1]

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