Mitochondrial Oxidative Stress Alters a Pathway in Caenorhabditis elegans Strongly Resembling That of Bile Acid Biosynthesis and Secretion in Vertebrates

Abstract

Mammalian bile acids (BAs) are oxidized metabolites of cholesterol whose amphiphilic properties serve in lipid and cholesterol uptake. BAs also act as hormone-like substances that regulate metabolism. The Caenorhabditis elegans clk-1 mutants sustain elevated mitochondrial oxidative stress and display a slow defecation phenotype that is sensitive to the level of dietary cholesterol. We found that: 1) The defecation phenotype of clk-1 mutants is suppressed by mutations in tat-2 identified in a previous unbiased screen for suppressors of clk-1. TAT-2 is homologous to ATP8B1, a flippase required for normal BA secretion in mammals. 2) The phenotype is suppressed by cholestyramine, a resin that binds BAs. 3) The phenotype is suppressed by the knock-down of C. elegans homologues of BA–biosynthetic enzymes. 4) The phenotype is enhanced by treatment with BAs. 5) Lipid extracts from C. elegans contain an activity that mimics the effect of BAs on clk-1, and the activity is more abundant in clk-1 extracts. 6) clk-1 and clk-1;tat-2 double mutants show altered cholesterol content. 7) The clk-1 phenotype is enhanced by high dietary cholesterol and this requires TAT-2. 8) Suppression of clk-1 by tat-2 is rescued by BAs, and this requires dietary cholesterol. 9) The clk-1 phenotype, including the level of activity in lipid extracts, is suppressed by antioxidants and enhanced by depletion of mitochondrial superoxide dismutases. These observations suggest that C. elegans synthesizes and secretes molecules with properties and functions resembling those of BAs. These molecules act in cholesterol uptake, and their level of synthesis is up-regulated by mitochondrial oxidative stress. Future investigations should reveal whether these molecules are in fact BAs, which would suggest the unexplored possibility that the elevated oxidative stress that characterizes the metabolic syndrome might participate in disease processes by affecting the regulation of metabolism by BAs.

A novel sphingolipid-TORC1 pathway critically promotes postembryonic development in Caenorhabditis elegans

“…(2) sptl-1(−) disrupts all sphingolipid biosynthesis and its phenotype is, in contrast to elo-5(−) , highly pleiotropic, as animals showed various morphological and growth defects and die at various larval stages. (3) tat-2 does not exclusively function with mmBCFA-containing lipids; it is also a critical player in steroid metabolism as exemplified by a recent article (Liu et al, 2012). Therefore, the link between mmBCFA and sphingolipids through their interactions with tat-2 could be indirect and the partial suppression of sptl-1(−) by tat-2(−) could be due to suppression of mmBCFA-unrelated functions of sphingolipids.…”

The Retrograde Response

“…This picture is further complicated by the fact that disruption of the worm electron transport chain at different places can extend lifespan but have different associated phenotypes 108 . The same study showed that ROS signaling is involved, but in a distinct mechanism that incorporates bile acid-like mediators which exert hormonal effects 109 .…”

Mitochondria to nucleus signaling and the role of ceramide in its integration into the suite of cell quality control processes during aging

“…Another engages the mitochondrial unfolded protein response and the transcription factors UBL-5 and DVE-1 (Durieux, et al, 2011), while the third is mediated by the predicted homeobox transcription factor CEH-23 (Walter, et al, 2011). The phenotypes associated with the lifespan extension afforded by mitochondrial dysfunction in the worm can be varied (Yang and Hekimi, 2010), and they can incorporate hormonal effects by bile acid-related species (Liu, et al, 2012). Similar to the worm studies, knockdown of respiratory chain components in Drosophila also extends lifespan (Copeland, et al, 2009), as does defective coenzyme Q synthesis (Liu, et al, 2011), but the signaling pathways are not known.…”