Mitochondrial caspase keeps autophagy in flux

Many cellular stresses, including starvation, induce cells to up-regulate the process of autophagy, in which cytoplasmic content is engulfed into autophagosomes and delivered to lysosomes for degradation. Autophagy can promote cell homeostasis and survival by removing damaged proteins and organelles and recycling their breakdown products to enhance cell metabolism. On the other hand, autophagy can contribute to cell death by digesting components of the dying cell. Both of these functions are important during development, and DeVorkin et al. describe how the caspase Dcp-1 promotes autophagy during Drosophila oogenesis (1).

Drosophila egg chambers consist of an oocyte and a group of supportive nurse cells, surrounded by a layer of somatic follicle cells. Flies shut off egg production when nutrients are scarce, with midstage egg chambers undergoing cell death and degeneration (2). Autophagy is up-regulated in these egg chambers (3, 4), and in 2008 Sharon Gorski’s lab at the Genome Sciences Centre in Vancouver, British Columbia, found that the death-promoting caspase Dcp-1 was required for this starvation-induced increase in autophagosome formation (4). “It was quite a surprise to find that a classic apoptosis protein also controls autophagy,” Gorski says. “We wanted to explore the mechanism by which Dcp-1 does this.”

Gorski and colleagues, led by graduate student Lindsay DeVorkin, first ascertained that Dcp-1 regulates autophagic flux, or lysosome-mediated degradation of autophagosomes, in nutritionally starved egg chambers (1). In wild-type ovaries, autophagy occurred in both degenerating and nondegenerating egg chambers, indicating that it contributes to cell homeostasis as well as to starvation-induced cell death. But in starved egg chambers lacking Dcp-1, the number of autolysosomes—the product of autophagosome fusion with lysosomes—was greatly reduced, and a model autophagy substrate was not as efficiently degraded, confirming that the caspase promotes autophagic flux.

To investigate how Dcp-1 might accomplish this, DeVorkin et al. examined the protein’s subcellular localization and found that the full-length, inactive form of the caspase (pro–Dcp-1) concentrated inside mitochondria. “In the absence of Dcp-1, we observed an increase in mitochondria with an elongated morphology in both nutrient-rich and starvation conditions,” Gorski explains. Dcp-1 therefore helps maintain the normal, shorter morphology of mitochondria in vivo. In wild-type egg chambers, mitochondria only elongate in response to nutrient deprivation. “It was shown previously that mitochondrial elongation helps to sustain cellular ATP levels following starvation,” Gorski says. “That led us to look at ATP levels [in fly ovaries], and we observed an increase in ATP when we knocked out Dcp-1.”

Increased ATP levels can suppress autophagy, and, sure enough, when DeVorkin et al. blocked ATP production with the ATP synthase inhibitor oligomycin A, autophagy was no longer impaired in Dcp-1–deficient egg chambers.

“We found that Dcp-1 alters ATP levels by regulating a nucleotide translocase called SesB,” says Gorski. SesB exchanges ATP for ADP across the inner mitochondrial membrane. In wild-type egg chambers, the levels of SesB protein decreased in response to starvation, but, in the absence of Dcp-1, SesB levels were enhanced in both nutrient-rich and starvation conditions. This suggested that SesB suppresses autophagy, and, accordingly, the egg chambers of SesB-deficient Drosophila showed reduced amounts of ATP and increased levels of autophagy even when the flies were well fed. In addition, loss of the nucleotide translocase restored the Dcp-1 phenotype and autophagic flux in Dcp-1–deficient ovaries, indicating that the caspase promotes autophagy by inhibiting SesB.

“We could not find any evidence that Dcp-1 cleaves SesB,” says Gorski. “But we did find that the pro form of the caspase interacts with SesB in mitochondria, so we think that this interaction controls the stability of SesB.” This nonproteolytic function of Dcp-1 and the fact that autophagy occurs in nondegenerating egg chambers suggest that Dcp-1 promotes autophagy independently of its role in apoptosis. The researchers now want to investigate how Dcp-1 is regulated and how it controls the stability of SesB, as well as to determine whether the pathway is conserved in mammalian tissues.