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Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis (1-3). Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing (4). Although transcriptional mechanisms that regulate mitochondrial abundance are known (5), 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., To study the function of very long chain fatty acids, we analysed Drosophila lacking Elovl6 (refs 6, 7), the enzyme elongating C16 fatty acids to C18. Sequence analysis identified noa [...]

The total synthesis of the molluscan polypropionate (-)-crispatene is described. The synthesis features a palladium-catalyzed crosscoupling to establish a sensitive conjugated tetraene and its Lewis acid-catalyzed cycloisomerization to yield the bicyclo[3.1.0]hexene core of the natural product. The absolute configuration of (-)-crispatene and related molecules is established.