Editors' ChoiceCell Biology

Defended by Lipids

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Science Signaling  22 Apr 2014:
Vol. 7, Issue 322, pp. ec111
DOI: 10.1126/scisignal.2005397

In the nematode Caenorhabditis elegans, mitochondrial dysfunction triggers a set of responses associated with mitochondrial repair (UPRmt), drug detoxification, and detection of pathogens. The transcription factor ATFS-1 is sequestered and degraded in the mitochondria and, in response to mitochondrial stress, accumulates in the nucleus to activate the genes that mediate the mitochondrial stress response, including hsp-6 (see Wolff and Dillin). Using reporter genes for the three activated pathways and the avoidance behavior that worms experiencing mitochondrial stress exhibit toward bacteria, their normal food source, Liu et al. examined the C. elegans response to genetic or chemical disruption of mitochondrial function. An RNA interference screen identified 45 genes that, when knocked down, reduced the induction of reporter genes in response to mitochondrial stress. These genes included those encoding proteins involved in lipid metabolism, such as sptl-1 (encoding a serine palmitoyltransferase involved in sphingolipid and ceramide synthesis) and hmgs-1 (encoding HMG-CoA synthase, involved in mevalonate metabolism). Addition of a ceramide mixture, C24 ceramide alone, or a nuclear-targeted ATFS-1 rescued the induction of the UPRmt reporter in worms in which SPTL-1 was knocked down or pharmacologically inhibited. Furthermore, ceramide accumulated at the mitochondria in worms experiencing mitochondrial stress. Mevalonate supplementation rescued the induction of the mitochondrial stress response reporter in worms in which HMGS-1 was knocked down. Statins are drugs that inhibit the mevalonate pathway and are used to inhibit endogenous cholesterol synthesis in patients with high cholesterol, but these drugs can have a serious muscle-damaging side effect. Exposing the worms to statins impaired the induction of the UPRmt reporter. Thus, in addition to compromising mitochondrial function by inhibiting synthesis of a component needed for ATP synthesis, these drugs also inhibit the cell’s ability to respond to the impairment in mitochondrial function. Coculturing the worms with various species of bacteria native to their natural environment showed that several species disrupted induction of the UPRmt reporter. Thus, lipids are involved in signaling mitochondrial dysfunction and bacteria can interfere with this response.

Y. Liu, B. S. Samuel, P. C. Breen, G. Ruvkun, Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508, 406–410 (2014).[PubMed]

S. Wolff, A. Dillin, The stressful influence of microbes. Nature 508, 328–329 (2014). [PubMed]

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