Regulation of mitochondrial morphology and function by stearoylation of TFR1

Abstract

Mitochondria have essential functions within cells, and their dysfunction is linked to various disorders; here, the fatty acid stearic acid (C18:0), which is a dietary component, and the transferrin receptor (TFR1) are shown to regulate mitochondrial function. In a study of the regulation of mitochondrial function, Aurelio Teleman and colleagues find that the fatty acid stearic acid (C18:0) and the protein transferrin receptor (TFR1) are both mitochondrial regulators. C18:0 acts by stearoylating TFR1, thereby inhibiting its activation of JNK signalling and promoting mitochondrial fusion and function. C18:0 is a dietary component and, intriguingly, animal cells respond to both increases and decreases in C18:0 levels. Dietary supplementation with C18:0 enhances mitochondrial fusion in Drosophila, counteracting the mitochondrial dysfunction caused by genetic defects such as the loss of the Parkinson's associated genes Pink and Parkin in models of the disease. Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis1,2,3. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing4. Although transcriptional mechanisms that regulate mitochondrial abundance are known5, 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.