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During autophagy mitochondria elongate, are spared from degradation and sustain cell viability

Abstract

A plethora of cellular processes, including apoptosis, depend on regulated changes in mitochondrial shape and ultrastructure. The role of mitochondria and of their morphology during autophagy, a bulk degradation and recycling process of eukaryotic cells’ constituents, is not well understood. Here we show that mitochondrial morphology determines the cellular response to macroautophagy. When autophagy is triggered, mitochondria elongate in vitro and in vivo. During starvation, cellular cyclic AMP levels increase and protein kinase A (PKA) is activated. PKA in turn phosphorylates the pro-fission dynamin-related protein 1 (DRP1), which is therefore retained in the cytoplasm, leading to unopposed mitochondrial fusion. Elongated mitochondria are spared from autophagic degradation, possess more cristae, increased levels of dimerization and activity of ATP synthase, and maintain ATP production. Conversely, when elongation is genetically or pharmacologically blocked, mitochondria consume ATP, precipitating starvation-induced death. Thus, regulated changes in mitochondrial morphology determine the fate of the cell during autophagy.

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Figure 1: Mitochondrial elongation in response to autophagy.
Figure 2: Increased phosphorylation of Ser 637 of DRP1 during autophagy.
Figure 3: Mitochondrial elongation during starvation is mediated by the cAMP–PKA axis.
Figure 4: Elongated mitochondria are spared from degradation during starvation.
Figure 5: Mitochondrial elongation sustains cellular ATP production and viability during autophagy.
Figure 6: Mitochondrial elongation during starvation is associated with dimerization and activation of ATPase.
Figure 7: Density of cristae increases in mitochondria elongated during starvation.
Figure 8: Mitochondrial elongation induced by PKA determines cell fate during starvation.

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Acknowledgements

L.C.G. is the recipient of a ‘Bolsa de Doutoramento’ of the ‘Fundação para a Ciência e Tecnologia’, Portugal. L.S. is a Senior Telethon Scientist of the Dulbecco-Telethon Institute. This research was supported by Telethon Italy S02016, AIRC Italy, Swiss National Foundation SNF 31-118171. We thank D. Chan, K. Mihara, C. Blackstone and N. Mizushima for reagents and T. Pozzan for helpful discussions on mitochondrially targeted luciferase calibration.

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L.C.G. and L.S. conceived research, analysed data and wrote the manuscript. L.C.G., G.D.B. and L.S. carried out experiments and analysed data.

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Correspondence to Luca Scorrano.

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Gomes, L., Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13, 589–598 (2011). https://doi.org/10.1038/ncb2220

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