Nutrient and Stress-Induced Mitochondrial Hyperfusion Regulates Cell Death Pathways

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Zeng, Karen
Mitochondrial biology , Biochemistry , Amino acid metabolism
Mitochondria undergo constant cycles of remodelling to sustain normal cell function. As the major cellular metabolic hub, mitochondria are understood to require a precise balance of membrane fission and fusion to maintain mitochondrial genome integrity and levels of oxidative phosphorylation. Mitochondria have been shown to shift the balance of these two opposing pathways to drive a hyperfusion response following proteostasis stress conditions to avoid apoptosis. Importantly, in response to amino acid starvation, mitochondria have been reported to undergo fusion to form elongated structures that avoid degradation via mitophagy. Here, we aimed to study the signals controlling nutrient-dependent mitochondrial fusion and we attempted to reverse the elongation by supplementing three regulatory amino acids, glutamine, leucine, and arginine. Surprisingly, the addback of amino acids did not reverse the elongation, rather, led to stronger mitochondrial hyperfusion. The mechanisms regulating amino-acid dependent mitochondrial hyperfusion response were unknown. We confirmed that addback of amino acids led to metabolic reprogramming that upregulated nucleotide biosynthesis pathways, independent of mTORC1. Additionally, we found the loss of fumarate hydratase prevented amino acid induced mitochondrial hyperfusion, which suggested that amino acid metabolism via the TCA cycle mediates the mitochondrial hyperfusion response. Furthermore, enzymatic inhibition of inosine monophosphate dehydrogenase further blocked this hyperfusion response, indicating a key role of purine biosynthesis in mitochondrial remodelling. The functional role of mitochondrial hyperfusion has been linked to a pro-survival response and we also observed a similar suppression of programmed cell death upon amino acid-induced mitochondrial hyperfusion. These results suggest a novel metabolic mechanism is responsible for sensing cellular amino acids to regulate mitochondrial fusion and cell survival.
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