Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids

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Abdullah, Mahmud O. and Zeng, Run X. and Margerum, Chelsea L. and Papadopoli, David and Monnin, Cian and Punter, Kaylee B. and Chu, Charles and Al-Rofaidi, Mohammad and Al-Tannak, Naser F. and Berardi, Domenica and Rattray, Zahra and Rattray, Nicholas J.W. and Abraham, Sheela A. and Eskelinen, Eeva-Liisa and Watson, David G. and Avizonis, Daina and Topisirovic, Ivan and Chan, Edmond Y.W. (2022) Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids. Cell Reports, 40 (7). p. 111198. 111198. ISSN 2211-1247 (https://doi.org/10.1016/j.celrep.2022.111198)

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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.

ORCID iDs

Abdullah, Mahmud O. ORCID logoORCID: https://orcid.org/0000-0002-0620-7235, Zeng, Run X., Margerum, Chelsea L., Papadopoli, David, Monnin, Cian, Punter, Kaylee B., Chu, Charles, Al-Rofaidi, Mohammad ORCID logoORCID: https://orcid.org/0000-0003-4917-7678, Al-Tannak, Naser F., Berardi, Domenica, Rattray, Zahra ORCID logoORCID: https://orcid.org/0000-0002-8371-8549, Rattray, Nicholas J.W. ORCID logoORCID: https://orcid.org/0000-0002-3528-6905, Abraham, Sheela A., Eskelinen, Eeva-Liisa, Watson, David G. ORCID logoORCID: https://orcid.org/0000-0003-1094-7604, Avizonis, Daina, Topisirovic, Ivan and Chan, Edmond Y.W.;
CORE (COnnecting REpositories)