Regulation of mitochondrial morphology and function by Stearoylation of TfR1

Mitochondria are involved in a variety of cellular functions including ATP production, amino acid and lipid biogenesis and breakdown, signaling and apoptosis(1-3). Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer, and aging(4). Although transcriptional mechanisms regulating mitochondrial abundance are known(5), comparatively little is known about how mitochondrial function is regulated. We identify here the metabolite stearic acid (C18:0) and Transferrin Receptor (TfR1) as mitochondrial regulators. We elucidate a signaling pathway whereby C18:0 stearoylates TfR1, thereby inhibiting its activation of JNK signaling. 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 Parkinsons genes Pink or Parkin. This work identifies the metabolite C18:0 as a signaling molecule regulating mitochondrial function in response to diet.