Limits...
A Mutation in Caenorhabditis elegans NDUF-7 Activates the Mitochondrial Stress Response and Prolongs Lifespan via ROS and CED-4.

Rauthan M, Ranji P, Abukar R, Pilon M - G3 (Bethesda) (2015)

Bottom Line: Statins, i.e., cholesterol-lowering drugs that inhibit the rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase, are lethal to Caenorhabditis elegans even though this animal lacks the branch of the mevalonate pathway that leads to cholesterol synthesis.To better understand the effects of statins that are not related to cholesterol, we have adopted the strategy of isolating statin-resistant C. elegans mutants.We conclude that the nduf-7(et19) mutant allele causes an increase in reactive oxygen species that activate ATFS-1, hence UPR(mt)-mediated statin resistance, and extends life span via CED-4.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, S-405 30, Sweden.

No MeSH data available.


The mevalonate pathway and screening strategy leading to identification of the nduf-7(et19) allele. (A) Overview of the mevalonate pathway, its sub-branches, and site of action of two inhibitors, namely statins and bisphosphonates. (B) Outline of the screening strategy to isolate fluvastatin-resistant mutants and their identification through whole genome sequencing. (C) Alignment of the highest conserved region between NDUF-7 and its human homolog, NDUFS7. The mutation in the nduf-7(et19) mutant, i.e., Q194STOP, is marked in red
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4528320&req=5

fig1: The mevalonate pathway and screening strategy leading to identification of the nduf-7(et19) allele. (A) Overview of the mevalonate pathway, its sub-branches, and site of action of two inhibitors, namely statins and bisphosphonates. (B) Outline of the screening strategy to isolate fluvastatin-resistant mutants and their identification through whole genome sequencing. (C) Alignment of the highest conserved region between NDUF-7 and its human homolog, NDUFS7. The mutation in the nduf-7(et19) mutant, i.e., Q194STOP, is marked in red

Mentions: The mevalonate pathway is required for the synthesis of diverse biomolecules: cholesterol, an important membrane component as well as a precursor for several steroid hormones; coenzyme Q (CoQ), an antioxidant and part of the mitochondrial electron transport chain; isopentenyl adenosine, required for t-RNA modification; farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), lipid moieties needed for proper membrane association of proteins; and dolichols, essential for protein glycosylation (Goldstein and Brown 1990; Rauthan and Pilon 2011). The pathway has one main trunk and multiple sub-branches that synthesize the different metabolites (Figure 1A) (Rauthan and Pilon 2011). Inhibitors of this pathway, namely bisphosphonates and statins, are used in therapies to prevent loss of bone mass and to lower blood cholesterol levels (Buhaescu and Izzedine 2007) . Statins are the most widely used drugs to control cholesterol levels; they work by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA), a rate-limiting enzyme in the main trunk of the pathway. Statins have rare but adverse side effects ranging from severe muscle pain to massive muscle loss (rhabdomyolysis). The adverse effects of statins seem mostly unrelated to the lowered cholesterol levels and are more likely due to the limited production of other metabolites that depend on the mevalonate pathway for their synthesis (Harper and Jacobson 2007; Bełtowski et al. 2009).


A Mutation in Caenorhabditis elegans NDUF-7 Activates the Mitochondrial Stress Response and Prolongs Lifespan via ROS and CED-4.

Rauthan M, Ranji P, Abukar R, Pilon M - G3 (Bethesda) (2015)

The mevalonate pathway and screening strategy leading to identification of the nduf-7(et19) allele. (A) Overview of the mevalonate pathway, its sub-branches, and site of action of two inhibitors, namely statins and bisphosphonates. (B) Outline of the screening strategy to isolate fluvastatin-resistant mutants and their identification through whole genome sequencing. (C) Alignment of the highest conserved region between NDUF-7 and its human homolog, NDUFS7. The mutation in the nduf-7(et19) mutant, i.e., Q194STOP, is marked in red
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528320&req=5

fig1: The mevalonate pathway and screening strategy leading to identification of the nduf-7(et19) allele. (A) Overview of the mevalonate pathway, its sub-branches, and site of action of two inhibitors, namely statins and bisphosphonates. (B) Outline of the screening strategy to isolate fluvastatin-resistant mutants and their identification through whole genome sequencing. (C) Alignment of the highest conserved region between NDUF-7 and its human homolog, NDUFS7. The mutation in the nduf-7(et19) mutant, i.e., Q194STOP, is marked in red
Mentions: The mevalonate pathway is required for the synthesis of diverse biomolecules: cholesterol, an important membrane component as well as a precursor for several steroid hormones; coenzyme Q (CoQ), an antioxidant and part of the mitochondrial electron transport chain; isopentenyl adenosine, required for t-RNA modification; farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), lipid moieties needed for proper membrane association of proteins; and dolichols, essential for protein glycosylation (Goldstein and Brown 1990; Rauthan and Pilon 2011). The pathway has one main trunk and multiple sub-branches that synthesize the different metabolites (Figure 1A) (Rauthan and Pilon 2011). Inhibitors of this pathway, namely bisphosphonates and statins, are used in therapies to prevent loss of bone mass and to lower blood cholesterol levels (Buhaescu and Izzedine 2007) . Statins are the most widely used drugs to control cholesterol levels; they work by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA), a rate-limiting enzyme in the main trunk of the pathway. Statins have rare but adverse side effects ranging from severe muscle pain to massive muscle loss (rhabdomyolysis). The adverse effects of statins seem mostly unrelated to the lowered cholesterol levels and are more likely due to the limited production of other metabolites that depend on the mevalonate pathway for their synthesis (Harper and Jacobson 2007; Bełtowski et al. 2009).

Bottom Line: Statins, i.e., cholesterol-lowering drugs that inhibit the rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase, are lethal to Caenorhabditis elegans even though this animal lacks the branch of the mevalonate pathway that leads to cholesterol synthesis.To better understand the effects of statins that are not related to cholesterol, we have adopted the strategy of isolating statin-resistant C. elegans mutants.We conclude that the nduf-7(et19) mutant allele causes an increase in reactive oxygen species that activate ATFS-1, hence UPR(mt)-mediated statin resistance, and extends life span via CED-4.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, S-405 30, Sweden.

No MeSH data available.