Manganese rescues adverse effects on lifespan and development in Podospora anserina challenged by excess hydrogen peroxide

Grimm, Carolin; Osiewacz, Heinz

doi:10.1016/j.exger.2015.01.042

Cited by 9 publications

(10 citation statements)

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“…To validate this latter role in P. anserina , we tested whether the reduced lifespan of a mutant overexpressing PaSod3 , encoding the mitochondrial superoxide dismutase, can be restored by the CYPD-inhibitor cyclosporine A. The mutant is characterized by increased ROS stress (Grimm and Osiewacz, 2015 ). Upon application of 0.05 μg/ml cyclosporine A to the growth medium, the growth rates of the wild type and PaSod3_OEx are significantly decreased, but do not differ from each other (Figure 3B ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, it was shown in myocytes from mice overexpressing CypD that autophagy is enhanced even under fed (non-starvation) conditions (Carreira et al, 2010 ). The pro-death role of PaCYPD-mediated mitochondrial permeability transition under severe stress is further emphasized by the lifespan-extending effect of the CYPD-inhibitor CsA in a P. anserina mutant overexpressing PaSod3 , which suffers from high oxidative stress and is also short-lived (Zintel et al, 2010 ; Grimm and Osiewacz, 2015 ). Although it is currently not explicitly shown whether death of this mutant is mediated by an autophagic or apoptotic type of PCD, the characteristics of the mutant suggest that it is likely that PaCYPD-mediated “type II” PCD is executed in this mutant.…”

Section: Discussionmentioning

confidence: 99%

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Cyclophilin D Is Involved in the Regulation of Autophagy and Affects the Lifespan of P. anserina in Response to Mitochondrial Oxidative Stress

et al. 2016

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The mitochondrial permeability transition pore plays a key role in programmed cell death and the induction of autophagy. Opening of the pore is regulated by the mitochondrial peptidyl prolyl-cis, trans-isomerase cyclophilin D (CYPD). Previously it was shown in the aging model organism Podospora anserina that PaCYPD abundance increases during aging and that PaCypD overexpressors are characterized by accelerated aging. Here, we describe a role of PaCYPD in the regulation of autophagy. We found that the accelerated aging phenotype observed in a strain overexpressing PaCypD is not metacaspase-dependent but is accompanied by an increase of general autophagy and mitophagy, the selective autophagic degradation of mitochondria. It thus is linked to what has been defined as “autophagic cell death” or “type II” programmed cell death. Moreover, we found that the previously demonstrated age-related induction of autophagy in wild-type aging depends on the presence of PaCYPD. Deletion of PaCypD leads to a decrease in autophagy in later stages of age and under paraquat-mediated oxidative stress. Finally, we report that PaCYPD is also required for mitohormesis, the beneficial effect of mild mitochondrial stress. Thus, PaCYPD plays a key role in the context-dependent regulation of pathways leading to pro-survival and pro-death effects of autophagy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cyclophilin D Is Involved in the Regulation of Autophagy and Affects the Lifespan of P. anserina in Response to Mitochondrial Oxidative Stress

et al. 2016

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“…In the current study we investigated PaSOD3, the mitochondrial manganese SOD of P. anserina . Previously, life-span shortening due to a limited detoxification of hydrogen peroxide generated by PaSOD3 has been demonstrated in a PaSod3 -overexpressing strain 9–10 . Surprisingly, the deletion of Pasod3 does not lead to accelerated aging and Pasod3 deletion strains are characterized by a wild-type-like life span.…”

Section: Discussionmentioning

confidence: 96%

“…Overexpression of PaSod3 coding for mitochondrial superoxide dismutase (in P. anserina SOD3, UniProtKB: B2AER6; in mammals SOD2, HGNC: 11180) active in the degradation of superoxide, leads to a decreased life span. This effect is due to insufficient hydrogen peroxide scavenging 9 . In contrast, the life span of a Pasod3 deletion strain ( Pasod3Δ ) does not significantly differ from that of the wild type 10 .…”

Section: Introductionmentioning

confidence: 93%

Stress-dependent opposing roles for mitophagy in aging of the ascomycete Podospora anserina

et al. 2017

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Mitochondrial dysfunction is causatively linked to organismal aging and the development of degenerative diseases. Here we describe stress-dependent opposing roles of mitophagy, the selective autophagic degradation of mitochondria, in aging and life-span control. We report that the ablation of the mitochondrial superoxide dismutase which is involved in reactive oxygen species (ROS) balancing, does not affect life span of the fungal aging model Podospora anserina, although superoxide levels are strongly increased and complex I-dependent respiration is impaired. This unexpected phenotype depends on functional autophagy, particularly mitophagy, which is upregulated during aging of this mutant. It identifies mitophagy as a prosurvival response involved in the control of mitohormesis, the well-known beneficial effect of mild mitochondrial oxidative stress. In contrast, excessive superoxide stress turns mitophagy to a prodeath pathway and leads to accelerated aging. Overall our data uncover mitophagy as a dynamic pathway that specifically responds to different levels of mitochondrial oxidative stress and thereby affects organismal aging.

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“…The calpains cleavage site in SNAP-25 was expected to be situated at the C-terminal [17], therefore the full length SNAP-25 protein was tested using SNAP-25-C-terminal antibodies, while the N-terminal fragments were tested by SNAP-25-N-terminal antibodies. Previous studies indicated that Mn caused a significant increase in [Ca 2+ ] i by disrupting oxidative phosphorylation and increasing the generation of reactive oxygen species (ROS) [7,34], the overproduction of which might inhibit the Adenosine Triphosphate (ATP)-driven plasma membrane calcium-pump (Ca 2+ -ATPase). This pump is of crucial importance in maintaining a low resting [Ca 2+ ] i concentration [35].…”

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein and Calpains Disrupt SNARE-Mediated Synaptic Vesicle Fusion During Manganese Exposure in SH-SY5Y Cells

Wang

Yan

et al. 2018

Cells

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Synaptic vesicle fusion is mediated by an assembly of soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs), composed of syntaxin 1, soluble NSF-attachment protein (SNAP)-25, and synaptobrevin-2/VAMP-2. Previous studies have suggested that over-exposure to manganese (Mn) could disrupt synaptic vesicle fusion by influencing SNARE complex formation, both in vitro and in vivo. However, the mechanisms underlying this effect remain unclear. Here we employed calpeptin, an inhibitor of calpains, along with a lentivirus vector containing alpha-synuclein (α-Syn) shRNA, to examine whether specific SNAP-25 cleavage and the over-expression of α-Syn disturbed the formation of the SNARE complex in SH-SY5Y cells. After cells were treated with Mn for 24 h, fragments of SNAP-25-N-terminal protein began to appear; however, this effect was reduced in the group of cells which were pre-treated with calpeptin. FM1-43-labeled synaptic vesicle fusion decreased with Mn treatment, which was consistent with the formation of SNARE complexes. The interaction of VAMP-2 and α-Syn increased significantly in normal cells in response to 100 μM Mn treatment, but decreased in LV-α-Syn shRNA cells treated with 100 μM Mn; similar results were observed in terms of the formation of SNARE complexes and FM1-43-labeled synaptic vesicle fusion. Our data suggested that Mn treatment could increase [Ca2+]i, leading to abnormally excessive calpains activity, which disrupted the SNARE complex by cleaving SNAP-25. Our data also provided convincing evidence that Mn could induce the over-expression of α-Syn; when combined with VAMP-2, α-Syn prevented VAMP-2 from joining the SNARE complex cycle.

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Manganese rescues adverse effects on lifespan and development in Podospora anserina challenged by excess hydrogen peroxide

Cited by 9 publications

References 45 publications

Cyclophilin D Is Involved in the Regulation of Autophagy and Affects the Lifespan of P. anserina in Response to Mitochondrial Oxidative Stress

Cyclophilin D Is Involved in the Regulation of Autophagy and Affects the Lifespan of P. anserina in Response to Mitochondrial Oxidative Stress

Stress-dependent opposing roles for mitophagy in aging of the ascomycete Podospora anserina

Alpha-Synuclein and Calpains Disrupt SNARE-Mediated Synaptic Vesicle Fusion During Manganese Exposure in SH-SY5Y Cells

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