Mitochondrial regulation of cell death in the Drosophila ovary

Interactions between the Bcl-2 family proteins and the mitochondrial fission and fusion machinery regulate cell death in mammals and worms. In Drosophila, the Bcl-2 family proteins have not been shown to be major regulators of cell death. However, emerging evidence suggests that mitochondrial remodeling may be important in Drosophila cell death. We recently demonstrated a series of events that occur during follicle removal in the Drosophila ovary that included mitochondrial remodeling and clustering, followed by uptake and degradation in the follicle cells. Importantly, the Bcl-2 family proteins, mitochondrial dynamics, and autophagic proteins regulate these events.     

Cracking open cell death in the Drosophila ovary

The Drosophila melanogaster ovary is a powerful yet simple system with only a few cell types. Cell death in the ovary can be induced in response to multiple developmental and environmental signals. These cell deaths occur at distinct stages of oogenesis and involve unique mechanisms utilizing apoptotic, autophagic and perhaps necrotic processes. In this review, we summarize recent progress characterizing cell death mechanisms in the fly ovary.     

Mitochondrial regulation of apoptotic cell death

Mitochondria play a decisive role in the regulation of both apoptotic and necrotic cell death. Permeabilization of the outer mitochondrial membrane and subsequent release of intermembrane space proteins are important features of both models of cell death. The mechanisms by which these proteins are released depend presumably on cell type and the nature of stimuli. Of the mechanisms involved, mitochondrial permeability transition appears to be associated mainly with necrosis, whereas the release of caspase activating proteins during early apoptosis is regulated primarily by the Bcl-2 family of proteins. However, there is increasing evidence for interaction and co-operation between these two mechanisms. The multiple mechanisms of mitochondrial permeabilization may explain diversities in the response of mitochondria to numerous apoptotic stimuli in different types of cells.     

Mitochondrial dynamics in the regulation of neuronal cell death

Mitochondria undergo continuous fission and fusion events in physiological situations. Fragmentation of mitochondria during cell death has been shown to play a key role in cell death progression, including release of the mitochondrial apoptotic proteins. Ultrastructural changes in mitochondria, such as cristae remodeling, is also involved in cell death initiation. Here, we emphasize the important role of mitochondrial fission/fusion machinery in neuronal cell death. Unlike many other cell types such as immortalized cell lines, neurons are distinct morphologically and functionally. We will discuss how this uniqueness presents special challenges in the cellular response to neurotoxic stresses, and how this affects the mitochondrial dynamics in the regulation of cell death in neurons.     

Mitochondrial thioredoxin in regulation of oxidant-induced cell death

Mitochondrial thioredoxin (mtTrx) can be oxidized in response to inducers of oxidative stress; yet the functional consequences of the oxidation have not been determined. This study evaluated the redox status of mtTrx and its association to oxidant-induced apoptosis. Results showed that mtTrx was oxidized after exposure to peroxides and diamide. Overexpression of mtTrx protected against diamide-induced oxidation and cytotoxicity. Oxidation of mtTrx was also achieved by knocking down its reductase; and lead to increased susceptibility to cell death. The data indicate that the redox status of mtTrx is a regulatory mechanism underlying the vulnerability of mitochondria to oxidative injury.     

Eggs over easy: cell death in the Drosophila ovary

Programmed cell death is the most common fate of female germ cells in Drosophila and many animals. In Drosophila, oocytes form in individual egg chambers that are supported by germline nurse cells and surrounded by somatic follicle cells. As oogenesis proceeds, 15 nurse cells die for every oocyte that is produced. In addition to this developmentally regulated cell death, groups of germ cells or entire egg chambers may be induced to undergo apoptosis in response to starvation or other insults. Recent findings suggest that these different types of cell death involve distinct genetic pathways. This review focuses on progress towards elucidating the molecular mechanisms acting during programmed cell death in Drosophila oogenesis.     

Genetic regulation of programmed cell death in Drosophila

Programmed cell death plays an important role in maintaining homeostasis during animal development,and has been conserved in animals as different as nematoes and humans. Recent studies of Drosophila have provided valuadle information toward our understanding of genetic regulation of death.Different signals trigger the novel death regulators rpr,hid,and grim,that utilize the evolutionarily conserved iap and ark genes to modulate caspase function.Subsequent removal of dying cells also appears to be accomplished by conserved mechanisms.The similarity between Drosophila and human in cell death signaling pathways illustrate the promise of fruit flies as a model system to elucidatek the mechanisms underlying regulation of programmed cell death.     

Mitochondrial apoptotic pathways induced by Drosophila programmed cell death regulators

Multicellular organisms eliminate unwanted or damaged cells by cell death, a process essential to the maintenance of tissue homeostasis. Cell death is a tightly regulated event, whose alteration by excess or defect is involved in the pathogenesis of many diseases such as cancer, autoimmune syndromes, and neurodegenerative processes. Studies in model organisms, especially in the nematode Caenorhabditis elegans, have been crucial in identifying the key molecules implicated in the regulation and execution of programmed cell death. In contrast, the study of cell death in Drosophila melanogaster, often an excellent model organism, has identified regulators and mechanisms not obviously conserved in other metazoans. Recent molecular and cellular analyses suggest, however, that the mechanisms of action of the main programmed cell death regulators in Drosophila include a canonical mitochondrial pathway.     

Steroid regulation of programmed cell death during Drosophila development

Steroid hormones play an important role in the regulation of numerous physiological responses, but the mechanisms that enable these systemic signals to trigger specific cell changes remain poorly characterized. Recent studies of Drosophila illustrate several important features of steroid-regulated programmed cell death. A single steroid hormone activates both cell differentiation and cell death in different tissues and at multiple stages during development. While several steroid-regulated genes are required for cell execution, most of these genes function in both cell differentiation and cell death, and require more specific factors to kill cells. Genes that regulate apoptosis during Drosophila embryogenesis are induced by steroids in dying cells later in development. These apoptosis genes likely function downstream of hormone-induced factors to serve a more direct role in the death response. This article reviews the current knowledge of steroid signaling and the regulation of programmed cell death during development of Drosophila.     

Mitochondrial fusion is regulated by Reaper to modulate Drosophila programmed cell death

In most multicellular organisms, the decision to undergo programmed cell death in response to cellular damage or developmental cues is typically transmitted through mitochondria. It has been suggested that an exception is the apoptotic pathway of Drosophila melanogaster, in which the role of mitochondria remains unclear. Although IAP antagonists in Drosophila such as Reaper, Hid and Grim may induce cell death without mitochondrial membrane permeabilization, it is surprising that all three localize to mitochondria. Moreover, induction of Reaper and Hid appears to result in mitochondrial fragmentation during Drosophila cell death. Most importantly, disruption of mitochondrial fission can inhibit Reaper and Hid-induced cell death, suggesting that alterations in mitochondrial dynamics can modulate cell death in fly cells. We report here that Drosophila Reaper can induce mitochondrial fragmentation by binding to and inhibiting the pro-fusion protein MFN2 and its Drosophila counterpart dMFN/Marf. Our in vitro and in vivo analyses reveal that dMFN overexpression can inhibit cell death induced by Reaper or γ-irradiation. In addition, knockdown of dMFN causes a striking loss of adult wing tissue and significant apoptosis in the developing wing discs. Our findings are consistent with a growing body of work describing a role for mitochondrial fission and fusion machinery in the decision of cells to die.     

Mitochondrial control of cell death

In many instances, permeabilization of mitochondrial membranes is a rate-limiting step of apoptotic or necrotic cell demise. This has important consequences for the pathophysiology of cell death, as well as for its pharmacological control.     

Drosophila nemo is an essential gene involved in the regulation of programmed cell death

Nemo-like kinases define a novel family of serine/threonine kinases that are involved in integrating multiple signaling pathways. They are conserved regulators of Wnt/Wingless pathways, which may coordinate Wnt with TGFbeta-mediated signaling. Drosophila nemo was identified through its involvement in epithelial planar polarity, a process regulated by a non-canonical Wnt pathway. We have previously found that ectopic expression of Nemo using the Gal4-UAS system resulted in embryonic lethality associated with defects in patterning and head development. In this study we present our analyses of the phenotypes of germline clone-derived embryos. We observe lethality associated with head defects and reduction of programmed cell death and conclude that nmo is an essential gene. We also present data showing that nmo is involved in regulating apoptosis during eye development, based on both loss of function phenotypes and on genetic interactions with the pro-apoptotic gene reaper. Finally, we present genetic data from the adult wing that suggest the activity of ectopically expressed Nemo can be modulated by Jun N-terminal kinase (JNK) signaling. Such an observation supports the model that there is cross-talk between Wnt, TGFbeta and JNK signaling at multiple stages of development.     

Mitochondrial effectors in caspase-independent cell death

Activation of caspases is recognized as a key element in the apoptotic process. However, new evidence is drawing attention to the emergent role of cell death pathways where caspases are not involved. Recent advances in the molecular understanding of these new ways to die, called caspase-independent, have revealed that mitochondria play an important role via the release of proapoptotic proteins. The purpose of this review is to integrate, from a biological and structural point of view, the most recent advances in the knowledge of the main mitochondrial proapoptotic proteins involved in this cell death cascade. The origin of programmed cell death is discussed through these strongly conserved effectors.     

Mitochondrial intermembrane proteins in cell death

Apoptosis is a form of programmed cell death important in the development and tissue homeostasis of multicellular organisms. Mitochondria have, next to their function in respiration, an important role in the apoptotic-signaling pathway. Malfunctioning at any level of the cell is eventually translated in the release of apoptogenic factors from the mitochondrial intermembrane space resulting in the organized demise of the cell. Some of these factors, such as AIF and endonuclease G, appear to be highly conserved during evolution. Other factors, like cytochrome c, have gained their apoptogenic function later during evolution. In this review, we focus on the role of cytochrome c, AIF, endonuclease G, Smac/DIABLO, Omi/HtrA2, Acyl-CoA-binding protein, and polypyrimidine tract-binding protein in the initiation and modulation of cell death in different model organisms. These mitochondrial factors may contribute to both caspase-dependent and caspase-independent processes in apoptotic cell death.