title: Regulation of mitochondrial morphology and function by stearoylation of TFR1.
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.
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Deniz
authors.initials: D
authors.lastname: Senyilmaz
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Virtue
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xu
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
authors.forename: Chong Yew
authors.initials: CY
authors.lastname: Tan
authors.affiliation: The Department of Biochemistry, Tennis Court Road, Cambridge CB2 1GA, UK.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Aubry K
authors.initials: AK
authors.lastname: Miller
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.|Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Aurelio A
authors.initials: AA
authors.lastname: Teleman
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D004032:Diet; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000081031:Fatty Acid Elongases; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects; D011990:Receptors, Transferrin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013229:Stearic Acids / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D029721:Drosophila Proteins; C527117:Marf protein, Drosophila; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D013229:Stearic Acids; D025521:Tumor Suppressor Proteins; C031183:stearic acid; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases; C487430:park protein, Drosophila