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Nature. 2015 Sep 3;525(7567):124-8. doi: 10.1038/nature14601. Epub 2015 Jul 27.

Regulation of mitochondrial morphology and function by stearoylation of TFR1.

Author information

1
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
3
The Department of Biochemistry, Tennis Court Road, Cambridge CB2 1GA, UK.
4
Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.

Abstract

Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. Although transcriptional mechanisms that regulate mitochondrial abundance are known, comparatively little is known about how mitochondrial function is regulated. Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. This leads to reduced ubiquitination of mitofusin via HUWE1, thereby promoting mitochondrial fusion and function. We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet.

PMID:
26214738
PMCID:
PMC4561519
DOI:
10.1038/nature14601
[Indexed for MEDLINE]
Free PMC Article

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