The shape of mitochondria is continuously defined by competing fusion and fission events. In addition to being degraded by a selective form of autophagy (mitophagy), mitochondria can participate in macroautophagy, although their role and morphology during this process is unclear. Scorrano and colleagues show that, during autophagy, unop-posed fusion triggers mitochondrial elongation, enabling mitochondria to resist autophagic degradation and prevent cell death.

In mammals, mitochondrial fusion is regulated by the dynamin-related GTPases optic atrophy 1 (OPA1), mitofusin 1 (MFN1) and MFN2, and mitochondrial fission is regulated by dynamin-related protein 1 (DRP1; also known as DNM1L). The authors first assessed the morphology of mitochon-dria during starvation-induced autophagy using confocal micro-scopy, observing that they become

elongated. As starvation-induced elongation was not observed in cells deficient for OPA1 or MFN1 and MFN2, the authors concluded that elongation depends on mitochondrial fusion.

The authors next hypothesized that, as less DRP1 was associated with mitochondria during starva-tion, mitochondrial fusion might predominate under these circum-stances. The protein kinase A (PKA)-mediated phosphorylation of DRP1 on Ser637 is known to prevent its translocation from the cytosol to the mitochondria. Upon starvation, phosphorylation of DRP1 at Ser637 was increased, and a PKA inhibitor blocked mitochondrial elongation. Furthermore, mitochondria did not elongate following the starvation of cells expressing a form of DRP1 that cannot be phosphorylated on Ser637. Thus, PKA phosphorylates DRP1 to prevent fission, which promotes mitochondrial elongation.

But what are the biological conse-quences of starvation-induced mito-chondrial elongation? Mitochondria in OPA1-null cells were degraded by mitophagy and showed signs of dysfunction following starvation, consuming ATP to maintain their membrane potential. By contrast, cells with elongated mitochondria were protected from mitophagy and maintained cellular ATP levels by increasin g the activity of ATP synthase and the number of cristae (internal compartments in the mitochondrial inner membrane that contain ATP synthase). In line with these data, cells null for OPA1, or MFN1 and MFN2, died more rapidly than wild-type or DRP1-null cells. The death of cells that could not undergo mitochondrial elongation could be rescued by an ATPase inhibitor, confirming that cells which are unable to undergo mito-chondrial elongation die as a result of depleted cellular ATP.

In short, following starvation, PKA phosphorylates DRP1 on Ser637 to prevent its translocation to mitochondria. Mitochondrial fusion prevails, leading to elongated mitochondria that are protected from autophagy and can maintain ATP production to promote cell viability.

Katharine H. Wrighton

ORIGINAL RESEARCH PAPER Gomes, L. C., Di Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nature Cell Biol. 10 Apr 2011 (doi:10.1038/ncb2220)FURTHER READING Westermann, B. Mitochondrial fusion and fission in cell life and death. Nature Rev. Mol. Cell Biol. 11, 872–884 (2010) | Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nature Rev. Mol. Cell Biol. 12, 9–14 (2011)

A U TO P H AGY

Shaping the fate of mitochondria

unopposed fusion triggers mitochondrial elongation, enabling mitochondria to resist autophagic degradation and prevent cell death.

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R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 12 | JUNE 2011

Nature Reviews Molecular Cell Biology | AOP, published online 29 April 2011; doi:10.1038/nrm3116

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