Editors' ChoicePhysiology

Compensating for the heat

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Sci. Signal.  02 Jun 2015:
Vol. 8, Issue 379, pp. ec141
DOI: 10.1126/scisignal.aac6707

Normal function of cellular membranes requires proper fluidity, which depends upon temperature and membrane lipid composition (see Fan and Evans). High temperature and abundant unsaturated lipids, both increase membrane fluidity. The nematode Caenorhabditis elegans maintains proper membrane fluidity in cold temperatures by increasing the expression of fat-7, which encodes a fatty acid desaturase. Ma et al. uncovered a mechanism by which heat induces compensatory changes in C. elegans membrane lipid composition. C. elegans grows optimally at 15 to 25°C and can survive heat shocks of 37°C. Worms lacking the acyl-CoA dehydrogenase ACDH-11 underwent developmental arrest at 25°C and showed reduced survival at 37°C. Compared with controls, acdh-11 mutants had increased membrane fluidity, increased expression of fat-7, and reduced abundance of the saturated fatty acid substrate of Fat-7. Treating animals with the membrane-stiffening chemical DMSO or introducing a mutation that reduced fat-7 expression rescued the growth arrest defect of acdh-11 mutants. Wild-type worms reared at 25°C showed increased expression of acdh-11 and decreased expression of fat-7 compared with those reared at 15°C or 20°C. ACHDs bind to fatty acids, and ACHD-11 bound with greatest affinity to fatty acids with alkyl chains of 10 to 12 carbons. The crystal structure of recombinant ACDH-11 purified from bacteria revealed the presence of C11 acyl-CoA (C11-CoA) in a deep pocket, where it made multiple hydrogen bonds with the protein. Fatty acids had not been added to the crystal growth solution, implying that ACDH-11 bound to C11-CoA during its production in the bacteria. The nuclear hormone receptor NHR-49 binds to fatty acids and promotes the expression of fat-7. Although a fluorescent fat-7 reporter was not active in untreated wild-type animals at 25°C, it was active when the growth medium was supplemented with C11 or C12 fatty acids. Knocking down nhr-49 by RNA interference prevented C11 and C12 fatty acids from stimulating expression of the fat-7 reporter in wild-type animals and reduced expression of the fat-7 reporter in achd-11 mutants. These results suggest a model in which high temperature induces the production of ACHD-11, which sequesters C11 and C12 fatty acids, thereby preventing activation of NHR-49 and expression of fat-7. At cold temperatures, NHR-49 promotes the expression of fat-7 to maintain membrane fluidity. Maintaining membrane fluidity under changing temperatures is especially important in ectotherms like C. elegans, but ACHDs may also play a role in regulating membrane fluidity in humans because mutations in ACHDs are associated with fatty acid oxidation disorders that are exacerbated by high temperature.

D. K. Ma, Z. Li, A. Y. Lu, F. Sun, S. Chen, M. Rothe, R. Menzel, F. Sun, H. R. Horvitz, Acyl-CoA dehydrogenase drives heat adaptation by sequestering fatty acids. Cell 161, 1152–1163 (2015). [PubMed]

W. Fan, R. M. Evans, Turning up the heat on membrane fluidity. Cell 161, 962–963 (2015). [PubMed]