Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids

Mahmud O. Abdullah, Run X. Zeng, Chelsea L. Margerum, David Papadopoli, Cian Monnin, Kaylee B. Punter, Charles Chu, Mohammad Al-Rofaidi, Naser F. Al-Tannak, Domenica Berardi, Zahra Rattray, Nicholas J.W. Rattray, Sheela A. Abraham, Eeva-Liisa Eskelinen, David G. Watson, Daina Avizonis, Ivan Topisirovic, Edmond Y.W. Chan

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Abstract

The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial fusion as a means to evade mitophagy. Surprisingly, further supplementation of glutamine (Q), leucine (L), and arginine (R) did not reverse, but produced stronger mitochondrial hyperfusion. Interestingly, the hyperfusion response to Q + L + R was dependent upon mitochondrial fusion proteins Mfn1 and Opa1 but was independent of MTORC1. Metabolite profiling indicates that Q + L + R addback replenishes amino acid and nucleotide pools. Inhibition of fumarate hydratase, glutaminolysis, or inosine monophosphate dehydrogenase all block Q + L + R-dependent mitochondrial hyperfusion, which suggests critical roles for the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses further support the idea that supplemented Q promotes purine biosynthesis by serving as a donor of amine groups. We thus describe a metabolic mechanism for direct sensing of cellular amino acids to control mitochondrial fusion and cell fate.
Original languageEnglish
Article number111198
Pages (from-to)111198
Number of pages22
JournalCell Reports
Volume40
Issue number7
DOIs
Publication statusPublished - 16 Aug 2022

Keywords

  • breast cancer
  • metabolomics
  • cancer
  • mitochondria
  • amino acid sensing
  • stable isotope tracer
  • glutamine
  • leucine
  • hyperfusion
  • Mfn2
  • Mfn1
  • Opa1
  • Drp1

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