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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetyltransferases / deficiency
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Animals
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Antigens, CD / metabolism*
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Diet
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Drosophila Proteins / deficiency
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster / cytology*
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Drosophila melanogaster / drug effects
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism*
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Fatty Acid Elongases
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HeLa Cells
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Larva / drug effects
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Larva / genetics
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Larva / metabolism
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Membrane Proteins / metabolism
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Mitochondria / drug effects
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondria / pathology
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Mitochondrial Dynamics / drug effects
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Receptors, Transferrin / metabolism*
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Signal Transduction / drug effects
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Stearic Acids / administration & dosage
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Stearic Acids / metabolism*
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Stearic Acids / pharmacology
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Tumor Suppressor Proteins
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination / drug effects
Substances
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Antigens, CD
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CD71 antigen
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Drosophila Proteins
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Marf protein, Drosophila
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Membrane Proteins
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Receptors, Transferrin
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Stearic Acids
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Tumor Suppressor Proteins
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stearic acid
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Acetyltransferases
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Fatty Acid Elongases
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HUWE1 protein, human
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Ubiquitin-Protein Ligases
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JNK Mitogen-Activated Protein Kinases
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park protein, Drosophila