Regulation of mitochondrial hyperfusion by ULK1-dependent sensing of amino acids

Identification: Chan, Edmond


Description

Regulation of mitochondrial hyperfusion by ULK1-dependent sensing of amino acids
 
Mahmud O. Abdullah1, Laura E. Gallagher1, Edmond Y.W. Chan1
1Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde
      
Mitochondria undergo constant membrane remodelling as part of their normal physiologic function.  Mitochondrial fission is critical for mitosis, apoptosis and degradation via mitophagy.  On the other hand, mitochondrial fusion has been proposed to allow content mixing, sustain mitochondrial fitness and avoid mitophagy.  
 
Here, while studying nutrient control of mitophagy, we observed that amino acid starvation promoted mitochondrial fusion, as expected.  We aimed to further dissect details of the amino acid signals.  Since key amino acids are detected by cellular sensors to activate MTORC1, we investigated these amino acids, namely glutamine (Gln), leucine (Leu) and arginine (Arg).  Surprisingly, we found that addback of Gln+Leu+Arg further promoted hyperfusion resulting in mitochondria over 2x the length produced by amino acid starvation.  Gln+Leu+Arg-dependent MTORC1 re-activation required growth factors to signal via the TSC1/2-Rheb pathway.  However, the ability of Gln+Leu+Arg-addback to stimulate mitochondrial hyperfusion was independent of serum and was not blocked by an MTOR inhibitor.  To characterize this response, we could confirm that Gln+Leu+Arg-dependent mitochondrial hyperfusion was strongly blocked by knockout of Mfn1 or Opa1.  Mitochondrial fusion can also be promoted via inhibition of Drp1-dependent fission.  However, Gln+Leu+Arg-driven hyperfusion did not involve phosphorylation changes on S616 and S637, the two sites that regulate Drp1.  In exploring the signaling, we found that the ULK1 autophagy initiation kinase complex was critical for promoting amino acid-dependent hyperfusion.  Targeting the ULK1/2 complex by gene knockout, CRISPR-mediated targeting or with inhibitors all blocked the ability of mitochondria to sense the stimulatory amino acids.  Targeting downstream autophagy pathways such as ATG5 did not block mitochondrial remodeling.
 
Our results therefore suggest a new mechanism linking cellular amino acids directly to the control of mitochondrial fusion.  This mechanism is critically dependent on the ULK1/2 signalling pathway, which also controls early steps of mitophagy and nutrient-dependent autophagy.  ULK1/2 thus plays a key role in orchestrating mitochondrial dynamics and maintenance.
 

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