title: Mitochondrial changes in ageing Caenorhabditis elegans--what do we learn from superoxide dismutase knockouts?
abstract: One of the most popular damage accumulation theories of ageing is the mitochondrial free radical theory of ageing (mFRTA). The mFRTA proposes that ageing is due to the accumulation of unrepaired oxidative damage, in particular damage to mitochondrial DNA (mtDNA). Within the mFRTA, the "vicious cycle" theory further proposes that reactive oxygen species (ROS) promote mtDNA mutations, which then lead to a further increase in ROS production. Recently, data have been published on Caenorhabditis elegans mutants deficient in one or both forms of mitochondrial superoxide dismutase (SOD). Surprisingly, even double mutants, lacking both mitochondrial forms of SOD, show no reduction in lifespan. This has been interpreted as evidence against the mFRTA because it is assumed that these mutants suffer from significantly elevated oxidative damage to their mitochondria. Here, using a novel mtDNA damage assay in conjunction with related, well established damage and metabolic markers, we first investigate the age-dependent mitochondrial decline in a cohort of ageing wild-type nematodes, in particular testing the plausibility of the "vicious cycle" theory. We then apply the methods and insights gained from this investigation to a mutant strain for C. elegans that lacks both forms of mitochondrial SOD. While we show a clear age-dependent, linear increase in oxidative damage in WT nematodes, we find no evidence for autocatalytic damage amplification as proposed by the "vicious cycle" theory. Comparing the SOD mutants with wild-type animals, we further show that oxidative damage levels in the mtDNA of SOD mutants are not significantly different from those in wild-type animals, i.e. even the total loss of mitochondrial SOD did not significantly increase oxidative damage to mtDNA. Possible reasons for this unexpected result and some implications for the mFRTA are discussed.
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. jan_gruber@nus.edu.sg
authors: Jan
authors: J
authors: Gruber
authors: Li Fang
authors: LF
authors: Ng
authors: Sheng
authors: S
authors: Fong
authors: Yee Ting
authors: YT
authors: Wong
authors: Soon Ann
authors: SA
authors: Koh
authors: Ce-Belle
authors: CB
authors: Chen
authors: Guanghou
authors: G
authors: Shui
authors: Wei Fun
authors: WF
authors: Cheong
authors: Sebastian
authors: S
authors: Schaffer
authors: Markus R
authors: MR
authors: Wenk
authors: Barry
authors: B
authors: Halliwell
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