Prevention of Apoptosis by Mitochondrial Phosphatase PGAM5 in the Mushroom Body Is Crucial for Heat Shock Resistance in Drosophila melanogaster

Abstract

The heat shock (HS) response is essential for survival of all organisms. Although the machinery of the HS response has been extensively investigated at the cellular level, it is poorly understood at the level of the organism. Here, we show the crucial role of the mushroom body (MB) in the HS response in Drosophila. Null mutants of the mitochondrial phosphatase Drosophila PGAM5 (dPGAM5) exhibited increased vulnerability to HS, which was reversed by MB-specific expression of the caspase inhibitor p35, and similar vulnerability was induced in wild-type flies by knockdown of MB dPGAM5. Elimination of the MB did not affect the HS response of wild-type flies, but did increase the resistance of dPGAM5-deficient flies to HS. Thus, the MB may possess an apoptosis-dependent toxic function, the suppression of which by dPGAM5 appears to be crucial for HS resistance.

The phosphatase Pgam5 antagonizes Wnt/β-Catenin signaling in embryonic anterior-posterior axis patterning

“…However, these phenotypes would also be explained by a loss of anterior cells (Offner et al, 2005). Necroptosis-promoting and -protective roles, as well as pro-and anti-apoptotic functions of Pgam5 have been described (Ishida et al, 2012;Lenhausen et al, 2016;Lu et al, 2016;Moriwaki et al, 2016;Zhou et al, 2012). However, we have not detected any local or global changes in cell death or apoptosis in Pgam5 morphant Xenopus embryos, indicating that regulation of cell death does not represent the major early developmental function of Pgam5 in Xenopus.…”

“…3B). Pgam5 has been functionally implicated in apoptosis, necroptosis and mitophagy, although it apparently acts as positive or negative regulator, depending on the experimental context (Chen et al, 2014;Ishida et al, 2012;Lenhausen et al, 2016;Lu et al, 2016;Moriwaki et al, 2016;Wang et al, 2012). Increased cell death in the anterior ectoderm might lead to a loss of head structures, while inhibition of cell death in early Xenopus embryos results in an expansion of neuroectoderm (Offner et al, 2005;Yeo and Gautier, 2003).…”

The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages

“…In addition, cleaved PGAM5 was implicated in apoptosis (31, 38). In contrast to these pro-apoptotic functions, Drosophila PGAM5 was shown to protect against heat shock-induced apoptosis of the mushroom body (39). The role of PGAM5 in necroptosis is similarly confusing.…”

Rhomboid Protease PARL Mediates the Mitochondrial Membrane Potential Loss-induced Cleavage of PGAM5

“…Interestingly, recent reports have suggested that PGAM5 is involved in multiple cell death pathways in a context-dependent manner. For example, we have recently reported that flies deficient in the Drosophila ortholog of mammalian PGAM5 (dPGAM5) are vulnerable to heat shock stress mainly because of increased apoptosis in neurons in the mushroom body, suggesting the role for PGAM5 in apoptosis regulation (41). On the other hand, dPGAM5 has recently been shown to act as an exacerbating factor for mitochondrial degeneration and dopaminergic neuronal cell death in the model of Parkinson disease induced by mutation of the Drosophila PINK1 gene (42).…”