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 language | English |
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Article number | 111198 |
Pages (from-to) | 111198 |
Number of pages | 22 |
Journal | Cell Reports |
Volume | 40 |
Issue number | 7 |
DOIs | |
Publication status | Published - 16 Aug 2022 |
Keywords
- breast cancer
- metabolomics
- cancer
- mitochondria
- amino acid sensing
- stable isotope tracer
- glutamine
- leucine
- hyperfusion
- Mfn2
- Mfn1
- Opa1
- Drp1