Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids
: Abdullah Mahmud O, Zeng Run X, Margerum Chelsea L, Papadopoli David, Monnin Cian, Punter Kaylee B, Chu Charles, Al-Rofaidi Mohammed, Al-Tannak Naser F, Berardi Domenica, Rattray Zahra, Rattray Nicholas JW, Abraham Sheela A, Eskelinen Eeva-Liisa, Watson David G, Avizonis Daina, Topisirovic Ivan, Chan Edmond YW
Publisher: Cell Press
: 2022
: Cell Reports
: Cell reports
: Cell Rep
: 111198
: 40
: 7
: 2211-1247
DOI: https://doi.org/10.1016/j.celrep.2022.111198
: https://doi.org/10.1016/j.celrep.2022.111198
: https://research.utu.fi/converis/portal/detail/Publication/176143851
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.
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