Effect of paraquat-induced oxidative stress on gene expression and aging of the filamentous ascomycete Podospora anserina

Wiemer, Matthias; Osiewacz, Heinz

doi:10.15698/mic2014.07.155

Cited by 23 publications

(18 citation statements)

References 61 publications

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“…In contrast, in comparison to the untreated wild type (Fig. 2B), the relative mean life span of paraquat-treated wild type 35 and Paatg1Δ was significantly increased (Fig. 7F and G).…”

Section: Resultsmentioning

confidence: 85%

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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“…In contrast, in comparison to the untreated wild type (Fig. 2B), the relative mean life span of paraquat-treated wild type 35 and Paatg1Δ was significantly increased (Fig. 7F and G).…”

Section: Resultsmentioning

confidence: 85%

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

et al. 2017

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“…We found that Metformin at a dose of 50mM rescued the lifespan deficit of GRU102 by normalizing its median lifespan to that of untreated GRU101 (Fig 4A). Metformin treatment also strengthened stress defense of GRU102, as seen in the reduced in percentage of dead GRU102 following challenge with Paraquat (Fig 4B), a herbicide that induces superoxide production 56 . While old GRU102 exhibited significantly impaired respiratory capacity, Metformin treatment significantly increased maximal respiratory capacity of GRU102 to a level that was, however, still lower than that of untreated GRU101 (Fig 4C).…”

Section: Resultsmentioning

confidence: 88%

Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta

Teo

Ravi

Barardo

et al. 2019

Preprint

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26Alzheimer's disease (AD) is the most common neurodegenerative disease affecting 27 the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in 28 the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced 29 mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by 30 expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on a 31 deeper analysis of these metabolic changes associated with A-induced mitochondrial 32 dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and 33 computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle 34 metabolism following even low-level Aβ expression. In particular, GRU102 show 35 reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate 36 dehydrogenase. These defects are associated with elevation of protein carbonyl 37 content specifically in mitochondria. Importantly, metabolic failure occurs before any 38 significant increase in global protein aggregate is detectable. Treatment with an anti-39 diabetes drug, Metformin, reverses A-induced metabolic defects, reduces protein 40 aggregation and normalizes the lifespan of GRU102. Our results point to metabolic 41 dysfunction as an early and causative event in AD pathology and a promising target 42 for intervention. 43 44 45 46 47 48 49 50 51 Introduction 52Alzheimer's disease (AD) is a debilitating neurodegenerative disease, that is clinically 53 characterized by the formation of amyloid-beta (A) plaques and aggregates of 54 hyperphosphorylated tau protein in the brain 1 . Even though AD is primarily a 55 neuronal disorder, perturbations in mitochondrial functions including energy 56 metabolism have consistently been observed not only in the brain 2-4 but also in non-57 neuronal cells derived from AD subjects, including in fibroblasts and platelets [5][6][7][8][9][10] . 58These findings form part of an emerging story that there is an important metabolic 59 component to the etiology of AD 11 , and that these metabolic defects may precede A 60 aggregate formation 12,13 . The metabolism-related hypothesis of AD therefore posits 61 that AD is, in part, mediated by impairments to the brain's insulin response, which 62 promotes oxidative stress and inflammation, similar to that seen in diabetes 11,14 . 63Intranasal insulin treatment has been shown to ameliorate AD pathology in a 64 transgenic rat model and to improve mild cognitive impairment (MCI) in patients [15][16][17][18] . 65 66Several animal studies have confirmed that oxidative stress, mitochondrial 67 dysfunction and metabolic alterations are early events in the pathophysiological 68 progression of AD. Energy deficits, reduction in mitochondrial membrane potential, 69 abnormal mitochondrial gene expression and increased oxidative stress have been 70 observed early in transgenic AD mice (2-3 months of age) well before the appearance 71 of A plaques 19,20 . The A-induced oxidative stress hypothesis further posits that A, 72 predomi...

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“…We compared well-known senescent markers in the two deletion strains and the wild type of defined chronological age. Apart from the recently identified ultrastructural reorganization of the IM, changes in mitochondrial morphotype 39 , reorganization of the mitochondrial DNA (mtDNA) 40 41 42 43 44 , an increase in hydroxide peroxide (H 2 O 2 ) release from cultures 39 45 and impairments in respiration 46 were analyzed as hallmarks of aging.…”

Section: Resultsmentioning

confidence: 99%

Impact of F1Fo-ATP-synthase dimer assembly factors on mitochondrial function and organismic aging

Rampello¹,

Stenger²,

Westermann³

et al. 2018

Microb Cell

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In aerobic organisms, mitochondrial F1Fo-ATP-synthase is the major site of ATP production. Beside this fundamental role, the protein complex is involved in shaping and maintenance of cristae. Previous electron microscopic studies identified the dissociation of F1Fo-ATP-synthase dimers and oligomers during organismic aging correlating with a massive remodeling of the mitochondrial inner membrane. Here we report results aimed to experimentally proof this impact and to obtain further insights into the control of these processes. We focused on the role of the two dimer assembly factors PaATPE and PaATPG of the aging model Podospora anserina. Ablation of either protein strongly affects mitochondrial function and leads to an accumulation of senescence markers demonstrating that the inhibition of dimer formation negatively influences vital functions and accelerates organismic aging. Our data validate a model that links mitochondrial membrane remodeling to aging and identify specific molecular components triggering this process.

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Effect of paraquat-induced oxidative stress on gene expression and aging of the filamentous ascomycete Podospora anserina

Cited by 23 publications

References 61 publications

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

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

Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta

Impact of F1Fo-ATP-synthase dimer assembly factors on mitochondrial function and organismic aging

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