Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis

Abstract

Mitochondrial dysfunction, with an estimated incidence of 1 in 10 000 live births, is among the most common genetically determined conditions. Missense mutations in the human NDUFV1 gene, which encodes the 51 kDa active site subunit of the NADH-ubiquinone oxidoreductase or complex I, can lead to severe neurological disorders. Owing to the rare and often sporadic nature of mitochondrial disorders, the mechanisms of pathogenesis of most mutations remain poorly understood. We have generated transgenic strains of Caenorhabditis elegans that express disease-causing mutations in the nuo-1 gene, the C. elegans homolog of the NDUFV1 gene. The transgenic strains demonstrate hallmark features of complex I dysfunction such as lactic acidosis and decreased NADH-dependent mitochondrial respiration. They are also hypersensitive to exogenous oxidative stress, suggesting that cellular defense mechanisms against reactive oxygen species are already taxed by an endogenous stress. The lactic acidosis induced by the NDUFV1 mutations could be partially corrected with the vitamins riboflavin and thiamine or with sodium dichloroacetate, an activator of the pyruvate dehydrogenase complex, resulting in significant increases in animal fitness. Surprisingly, cytochrome c oxidase activity and protein levels were reduced, establishing a connection between complexes I and IV. Our results indicate that complex I mutations exert their pathogenic effects in multiple ways: by impeding the metabolism of NADH, by increasing the production of reactive oxygen species, and by interfering with the function or assembly of other mitochondrial respiratory chain components.

Neurospora Strains Harboring Mitochondrial Disease-Associated Mutations in Iron-Sulfur Subunits of Complex I

“…The worm mutants demonstrated hallmark features of complex I dysfunction such as lactic acidosis and decreased NADH-dependent mitochondrial respiration, although the authors did not study the assembly of the mutated enzymes. Furthermore, the C. elegans mutants displayed a decrease in the assembly and/or activity of complex IV and hypersensitivity to oxidative stress (Grad and Lemire 2004). In agreement with the results observed in this system, we found that the A353V mutation has a more drastic effect on N. crassa complex I than the T435M mutation does, which results in an approximately twofold reduction in complex I amounts.…”

“…We assume that the mutant subunit is degraded at some stage before integration in complex I. Recently, C. elegans transgenic strains composing the two mutations in the 51-kDa subunit were generated as disease models (Grad and Lemire 2004). The worm mutants demonstrated hallmark features of complex I dysfunction such as lactic acidosis and decreased NADH-dependent mitochondrial respiration, although the authors did not study the assembly of the mutated enzymes.…”

“…As direct studies of human material are subject to strong restrictions and, in particular, many complex I patients die young, the development of nonhuman models of the diseases is very desirable. Research on mitochondrial complex I deficiency has been conducted in cell cultures (Hofhaus and Attardi 1993;Hofhaus et al 1996), the yeast Yarrowia lipolytica (Ahlers et al 2000), and Caenorhabditis elegans (Grad and Lemire 2004). Models of mutations in mitochondrial genes have been generated especially in prokaryotes (Lunardi et al 1998;Zickermann et al 1998) due to the specific difficulties associated with gene replacement in mitochondria.…”

Metabolic pathway profiling of mitochondrial respiratory chain mutants in C. elegans

“…This body of information may permit the development of a systems biology-based diagnostic approach to mitochondrial disease in human patients. C. elegans can also provide a system in which to test the efficacy of treatments for mitochondrial diseases [30], a class of disorders that has proved largely resistant to therapy.…”

Differential Impact of Environmental Stresses on the Pea Mitochondrial Proteome

“…Recently in Drosophila, overexpression of HSP22 has been shown to increase life span and resistance to oxidative stress (19), whereas underexpression decreases life span (20). Complex I of the respiratory chain is a known site of oxidative damage in mitochondria (5), but mutations of complex I can lead to increased stress tolerance and cell viability in plants (21,22) while often decreasing stress tolerance in animals leading to disease (23,24). This difference may reflect the presence of alternative NAD(P)H dehydrogenases in plant mitochondria (25).…”