Caenorhabditis elegans drp-1 and fis-2 Regulate Distinct Cell-Death Execution Pathways Downstream of ced-3 and Independent of ced-9

Breckenridge, David G.; Kang, Byung-Ho; Kokel, David; Mitani, Shohei; Staehelin, L. Andrew; Xue, Ding

doi:10.1016/j.molcel.2008.07.015

Cited by 131 publications

(149 citation statements)

References 55 publications

(112 reference statements)

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“…This finding suggests that the loss of mitochondrial energy production in fzo-1-deficient animals could also contribute to cell death in CoQ-depleted GABA neurons. Although mitochondrial fission has been linked to apoptosis in mammals, conflicting results have been obtained in C. elegans (39,40). However, our finding that DRP-1 is required for GABA neuron degeneration in C. elegans parallels results with mammalian cells showing that mitochondrial fission is a necessary step in experimental models of neurodegenerative disease resulting from mitochondrial injury.…”

Section: Mitochondrial Morphogenesis Protein Drp-1 Is Required For Thesupporting

confidence: 80%

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Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Earls

Hacker²,

Watson³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondria are key regulators of cell viability and provide essential functions that protect against neurodegenerative disease. To develop a model for mitochondrial-dependent neurodegeneration in Caenorhabditis elegans, we used RNA interference (RNAi) and genetic ablation to knock down expression of enzymes in the Coenzyme Q (CoQ) biosynthetic pathway. CoQ is a required component of the ATP-producing electron transport chain in mitochondria. We found that reduced levels of CoQ result in a progressive uncoordinated (Unc) phenotype that is correlated with the appearance of degenerating GABA neurons. Both the Unc and degenerative phenotypes emerge during late larval development and progress in adults. Neuron classes in motor and sensory circuits that use other neurotransmitters (dopamine, acetylcholine, glutamate, serotonin) and body muscle cells were less sensitive to CoQ depletion. Our results indicate that the mechanism of GABA neuron degeneration is calcium-dependent and requires activation of the apoptotic gene, ced-4 (Apaf-1). A molecular cascade involving mitochondrial-initiated cell death is also consistent with our finding that GABA neuron degeneration requires the mitochondrial fission gene, drp-1. We conclude that the cell selectivity and developmental progression of CoQ deficiency in C. elegans indicate that this model may be useful for delineating the role of mitochondrial dysfunction in neurodegenerative disease.cell death | disease | mitochondria | neurodegeneration | necrosis

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Section: Mitochondrial Morphogenesis Protein Drp-1 Is Required For Thesupporting

confidence: 80%

“…3D). DRP-1 (dynamin-related protein) has been shown to function in both mitochondrial fission (39) and in a ced-3-dependent and ced-9-independent cell death pathway (40). The drp-1 mutant blocked GABA neuron degeneration (Fig.…”

Section: Coq-1 Knockdown-induced Cell Death Depends On the Mitochondrialmentioning

confidence: 99%

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Earls

Hacker²,

Watson³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…elegans and D. melanogaster (Breckenridge et al, 2008;Fannjiang et al, 2004;Goyal et al, 2007;Jagasia et al, 2005). While ablation of Dnm1 in yeast and Drp1 in flies increased survival following death stimuli, overexpression of dominant negative Drp1 reduced developmental cell death in nematodes.…”

Section: Mitochondrial Fission During Apoptosis In Lower Organismsmentioning

confidence: 99%

“…Indeed a more recent study by Xue and colleagues comprehensively showed that loss of function mutations in fission and fusion genes in C. elegans had no effect on apoptotic cell death (Breckenridge et al, 2008). Instead they found that Drp1 and Fis1 promote the elimination of mitochondria in apoptotic cells indicating that these proteins play a role in the execution phase of apoptosis rather than the initiating phase.…”

Section: Mitochondrial Fission During Apoptosis In Lower Organismsmentioning

confidence: 99%

Mitochondrial fission/fusion dynamics and apoptosis

2010

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Mitochondria play an important role in the progression of apoptosis through the release of pro-apoptotic factors, such as cytochrome c, from the mitochondrial intermembrane space.During this process, mitochondrial networks are dramatically reorganised from long filamentous interconnected tubules into small punctate spheres. Whether remodelling of mitochondrial networks is necessary for apoptosis-associated cytochrome c release, or merely an accompanying process, has been a subject of debate. Here we discuss evidence for and against the role of mitochondrial fragmentation in the progression of apoptosis and highlight recent advances which indicate that mitochondrial fission is not a critical requirement for apoptosis-associated cytochrome c release. We also discuss an emerging role for Bcl-2 family members as regulators of mitochondrial fission and fusion dynamics, independent of the role of this family in the regulation of apoptosis.

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“…Moreover, recent studies performed in more physiological settings, failed to confirm any role for CED-9 or EGL-1 in the mitochondrial dynamics (fission and fusion) of C. elegans. 26,27 This represents an intensely debated topic, yet the overall tendency in the field is to admit the divorce between MOMP, which (at least in mammalian cells) is required for apoptosis, and mitochondrial fragmentation, which is dispensable for both MOMP and apoptosis. 28,29 ANT: a Novel Ingredient of the 'Core' Machinery A recent paper by Shen et al 3 now reveals that the constitutive mitochondrial membrane protein ANT is part of the 'core' machinery for apoptosis in C. elegans.…”

Section: The 'Core' Machinery For Cell Death Executionmentioning

confidence: 99%

Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery

2009

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Lethal mitochondrial membrane permeabilization has been depicted as the result of two fundamentally distinct processes, namely primary mitochondrial outer membrane permeabilization (MOMP) versus permeability transition (PT) ignited at the level of the mitochondrial inner membrane. MOMP and PT have been connected to apoptosis and necrosis, respectively. Moreover, it has been thought that MOMP was mediated by pro-apoptotic multidomain proteins of the Bcl-2 family (Bax and Bak), which would operate near-to-independently from the permeability transition pore complex (PTPC) composed by voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT) and cyclophilin D. A recent paper in Molecular and Cellular Biology now reveals the obligate contribution of one particular ANT isoform to the execution of developmental and homeostatic cell death in Caenorhabditis elegans. The physical and functional interaction between CED-9, the sole multidomain Bcl-2 protein of C. elegans, and ANT emphasizes the existence of an intricate, phylogenetically conserved crosstalk between Bcl-2 family proteins and constituents of the PTPC. In this issue of Cell Death and Differentiation, Malorni et al. further corroborate this notion by showing that type 2 transglutaminase (TG2) is essential for the correct assembly/function of ANT1, and that, at least in some experimental settings, TG2 might be required to enable and/or stabilize the pro-apoptotic association of Bax with ANT1. The 'core' machinery of apoptosis was discovered by screening Caenorhabditis elegans mutations that suppressed developmental cell death, yielding a number of genes whose mammalian equivalents also have an important function in physiological and disease-associated apoptosis. Once it has been transcriptionally upregulated, EGL-1 (the only BH3-only protein encoded by C. elegans) disrupts a molecular complex composed by CED-9 (a Bcl-2 ortholog localized in mitochondrial membranes) and CED-4 (the nematode counterpart of Apaf-1, which is also normally present at mitochondria). As a consequence, CED-4 becomes free to translocate to the nuclear envelope and to activate CED-3 (the worm caspase), thereby inducing apoptosis. 1,2 Now, a new protein, WAN-1, the nematode ortholog of mammalian adenine nucleotide translocase (ANT) has been added to the 'core' machinery. 3 The 'Core' Machinery for Cell Death ExecutionThe scenario of a conserved cell death 'core' machinery composed by EGL-1, CED-9, CED-4 and CED-3 has been dominating the field of cell death research up to the point that some investigators suggested the existence of a ternary molecular complex made by Apaf-1, caspase-9 and the Bcl-2 homolog Bcl-X L also in mammalian cells, 4,5 which turned out to be a bold artifact. [6][7][8] Similarly, the idea that EGL-1, CED-9, CED-4 and CED-3 might have other functions than mediating cell death (EGL-1 as an inducer of autophagy, 9 CED-4 as part of the intra-S-phase DNA damage checkpoint, 2 CED-3 in the innate immune system 10 ) met incredulity and resistance. Prominent ...

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Caenorhabditis elegans drp-1 and fis-2 Regulate Distinct Cell-Death Execution Pathways Downstream of ced-3 and Independent of ced-9

Cited by 131 publications

References 55 publications

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Mitochondrial fission/fusion dynamics and apoptosis

Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery

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