Regulation of mitochondrial morphology and function by stearoylation of TFR1

Abstract

SummaryMitochondria are involved in a variety of cellular functions including ATP production, amino acid and lipid biogenesis and breakdown, signaling and apoptosis1-3. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer, and aging4. Although transcriptional mechanisms regulating mitochondrial abundance are known5, 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.

Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis

“…Jian et al reported that Tfr1 interacts with Src, and phosphorylation of Tfr1 residue 20 Y by Src decreases apoptosis and promotes cancer cell survival (37). GA induced phosphorylation of p38, JNK, and ERK in a manner that was independent of Tf binding and iron uptake and Tfr1 mutants at 20 Y were more susceptible to GA. Senyilmaz et al reported a similar signaling activity of Tfr1, which also involved activation of JNK signaling and was modulated by stearic acid (38). JNK signaling has been linked to intestinal epithelial homeostasis and villus length (39).…”

Mitochondrial fusion, fission, and mitochondrial toxicity

“…Conversely, superfluous nutrients can cause increased fragmentation (Molina et al 2009); these changes are quickly reversible with altered calorie availability (Schrepfer and Scorrano 2016). Additionally, a recent study has demonstrated that the fatty acid metabolite, stearic acid (C18:0), reversed mitochondrial fragmentation by limiting ubiquitination and degradation of mitofusins by HECT, UBA, and WWE domain containing E3 ubiquitin protein ligase (Senyilmaz et al 2015). However, many of these studies have been carried out in vitro , and the extent to which SIMH occurs in vivo , and what other factors may regulate its occurrence, are unclear; for example, we recently failed to observed SIMH with chronic, non-lethal arsenic exposure in Caenorhabditis elegans (Luz et al 2017).…”

A role for iron deficiency in dopaminergic neurodegeneration

“…In nonerythroid cells, iron defects resulting from TfR1 deficiency result in metabolic defects, defective mitophagy, and increase in gene expression associated with cell death (16,17). A noncanonical function for TfR1, not related to iron metabolism per se, has been recently reported in some tissues (15,18).…”