'Stear'ing Down the New Mitochondrial Regulatory Pathway

Everyone knows that mitochondria are the powerhouse of the cell. However, mitochondria are also involved in a variety of cellular processes such as amino acid and lipid production and breakdown. Mitochondria undergo cycles of fission and fusion, regulated by proteins known as mitofusin’s, which create a dynamic mitochondrial network. Dysfunction of the mitochondrial network has been implicated in many different neurological diseases such as Parkinson’s. This study presents the first ever evidence of stearic acid (C18) as a mitochondrial regulator with potential therapeutic implications.

Researchers serendipitously discovered that drosophila lacking Elovl6, the elongase that converts C16 to C18, were highly sensitive to mitotoxins implicating the role of C18 in mitochondrial regulation. Elolv6– cells, in both humans and drosophila, display reduced respiration and a highly fragmented mitochondrial network. Alongside mitofusin (mfn) knockout experiments this indicates that C18 serves as an upstream regulator of mitofusion functions. Immunoprecipitation of mfn from C18 deficient cells displayed hyperubiquinitization which was rescued by the deletion of the ubiquitin ligase, HUWE1. Only mfn phosphorylated by JNK are ubiquitinated by HUWE1. Lipid pull-down and immunoblotting indicated that C18 covalently binds to TFR-1 and knockdown indicated that TFR-1 mediates mitochondrial fragmentation via JNK signaling, which is inhibited by TFR-1 stearoylation. Thus concluding that stearates TFR-1 which inhibits JNK/HUWE1 mediated ubiquitination promoting mfn regulation of the mitochondrial network. Remarkably, in a drosophila Parkinson’s disease model, C18 supplementation improved neurological symptoms which indicating the potential therapeutic role of dietary C18 and implications of this signaling pathway for future therapeutic targets.

 

Senyilmaz, D. et al. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature 525, 124–128 (2015).

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