Editors' ChoicePhysiology

Hypoxia induces mitochondrial protein misfolding

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Science Signaling  25 Aug 2015:
Vol. 8, Issue 391, pp. ec239
DOI: 10.1126/scisignal.aad2794

Mitochondria mediate cellular responses to hypoxia through redox and calcium signaling mechanisms. Activation of the mitochondrial unfolded protein response (mtUPR) is important for protecting organisms from the effects of aging. Kaufman et al. found that the mtUPR also protects organisms from the damaging effects of hypoxia. When Caenorhabditis elegans were exposed to sublethal hypoxia for 12 hours, mitochondria in intestinal cells adopted an abnormal morphology and most became depolarized, aggregates of misfolded proteins accumulated in the mitochondria of various cell types, and the mtUPR was induced. Experimental induction of the mtUPR before a 20-hour exposure to hypoxia improved the survival of wild-type worms in a manner that depended on the transcription factor ATFS-1, which activates the expression of nuclear genes involved in the mtUPR. Worms homozygous for alleles of atfs-1 that cause constitutive nuclear localization were also protected from hypoxia-induced death. Surprisingly, activation of the mtUPR after hypoxia exposure also protected animals from hypoxia-induced lethality. The protective effect of the mtUPR was not cell autonomous because inducing the mtUPR specifically in the intestine or in neurons rescued hypoxia-induced pharyngeal paralysis. (Pharyngeal pumping requires only pharyngeal myocytes, not intestinal cells or neurons.) At the cellular level, inducing the mtUPR either before or after hypoxia exposure restored mitochondrial morphology and reduced the number of mitochondria that contained protein aggregates. These results identify mitochondrial misfolding as an early event in hypoxia and establish the importance of the mtUPR in mitigating hypoxia-induced injury at both the organismal and cellular levels.

D. M. Kaufman, C. M. Crowder. Mitochondrial proteostatic collapse leads to hypoxic injury. Curr Biol. 25, 2171–2176 (2015). [PubMed]

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