S 9 Mitochondria as a Therapeutic Target

S9 Mitochondria as a Therapeutic Target 9L.1 Stearoyl-CoA desaturase and insulin signaling — What is the molecular switch? Agnieszka Dobrzyn Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland E-mail: [email protected] Insulin resistance, an impaired biological response to circulating insulin, is a disorder common to most of the obesity-related diseases and, as such, represents an important target of medical research. The precise etiology of impaired insulin action in obese people is still unknown; however, an increasing body of evidence indicates that it may be associated with alterations in intracellular lipid metabolism. Insulin-resistant humans and animals accumulate significant amounts of lipids not only in the adipose tissue, but also in liver, muscle and other peripheral tissues. Storage of even a modest caloric surplus in lean, insulin sensitive tissues leads to insulin resistance. Altered lipid metabolism as seen in the insulin-resistant states largely depends on the aberrant expression of genes encoding key metabolic enzymes. Consequently, several enzymes regulating lipidmetabolism have been recently proposed as therapeutic targets. One of these enzymes, stearoyl-CoA desaturase (SCD), appears to be of special significance, because SCD1 is the major gene target of leptin, which is the central mediator regulating energy homeostasis and a known insulinsensitizer. Increasing evidence suggests that SCD, the rate limiting enzyme of monounsaturated fatty acid biosynthesis, is an important factor in the pathogenesis of lipid-induced insulin resistance. Mice with a targeted disruption of the SCD1 gene have improved glucose tolerance compared to wild-type mice, despite lower fasting plasma insulin levels. Increased SCDactivity has been found in insulin resistant humans and animals, whereas SCD1 deficiency attenuates both dietand genetically-induced impairment of insulin action. In skeletal muscle and in brown adipose tissue, basal tyrosine phosphorylation of the IRS1 and IRS2, the association of both IRS1 and IRS2 with the ap85 subunit of phosphatidyl-inositol 3-kinase, the phosphorylation of Akt and membrane GLUT4 translocation are all elevated in SCD1−/− mice comparedwithwild-typemice. Our recent study showed that deletion of SCD1 gene protects muscle against lipid-induced insulin resistance. While the precise mechanism of SCD action on insulin signaling remains to be clarified, current findings on SCD point to a very promising novel strategy for the treatment of insulin resistance. doi:10.1016/j.bbabio.2010.04.236 9L.2 Mitochondrial fatty acid synthesis and respiration J. Kalervo Hiltunen, Kaija J. Autio, Melissa S. Schonauer, V.A. Samuli Kursu, Carol L. Dieckmann, Alexander J. Kastaniotis Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland Department of Biochemistry, University of Arizona, Tucson, Arizona, USA E-mail: [email protected] The dual localization of fatty acid synthesis (FAS) in eukaryotic cellsraises the question of why have eukaryotes maintained the FAS in themitochondria in additions to the “classic” cytoplasmic FAS. Themitochondrial FAS is composed of a discrete set of monofunctionalenzymes resembling the bacterial FAS system in contrast to theeukaryotic cytosolic multifunctional complex. Yeast cells deficient inmitochondrial FAS have rudimentary mitochondria and a respiratorydeficient phenotype, exhibit loss of spectrally detectable cytochromes,and are defective in mitochondrial RNA processing [3,4]. One task ofthe mitochondrial FAS is to generate octanoyl-ACP which is used forlipoic acid synthesis. This is apparently also a conserved and essentialprocess in mammals. Lipoic acid is required for the function of severalmultienzyme complexes involved in the oxidative decarboxylation ofα-keto-acids and glycine. The mechanistic details of lipoic acidmetabolism are unclear in eukaryotes, despite two well-definedpathways for synthesis and covalent attachment of lipoic acid inprokaryotes. Recently we demonstrated the involvement of four genesin the synthesis and attachment of lipoic acid in Saccharomycescerevisiae. LIP2 and LIP5 are required for lipoylation of all three mito-chondrial target proteins: Lat1 and Kgd2, the respective E2 subunits ofpyruvate dehydrogenase and α-ketoglutarate dehydrogenase, andGcv3, the H protein of the glycine cleavage enzyme. LIP3, whichencodes a lipoate-protein ligase homolog, is necessary for lipoylationof Lat1 and Kgd2, and the enzymatic activity of Lip3 is essential for thisfunction. GCV3, encoding the H protein target of lipoylation, is itselfabsolutely required for lipoylation of Lat1 andKgd2 [5]. Recently piecesof evidence have been emerging which link the mtFAS pathway todisease in mammals. Our recent report on the development ofcardiomyopathy in mice overexpressing Etr1 established a possibleconnection between mtFAS and heart disease [1]. The expression of17βHSD8, encoding a subunit in KAR1 [2], has been reported to berepressed in kidney and liver of polycystic kidney disease mousemodels. References[1] Chen Z-J (2009a) Plos One 4: e5589.[2] Chen Z-J (2009b) FASEB J. 23: 3682-3691.[3] Hiltunen J K et-al. (2009) J. Biol. Chem. 284: 9011-9015.[4] Schonauer M S et-al. (2008) Mol. Cell. Biol. 28: 6646-6657.[5] Schonauer M S et-al. (2009) J. Biol. Chem. 284: 33234-33242. doi:10.1016/j.bbabio.2010.04.237