Hypersensitivity to oxygen and shortened lifespan in a
            <i>Drosophila</i>
            mitochondrial complex II mutant

Walker, David W.; Hájek, Petr; Muffat, Julien; Knoepfle, Daniel T.; Cornelison, Stephanie; Attardi, Giuseppe; Benzer, Seymour

doi:10.1073/pnas.0607918103

Cited by 98 publications

(108 citation statements)

References 27 publications

(31 reference statements)

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“…Both of these SDHB and SDHC mutants were associated with mild ROS production and with death or tumourigenesis, respectively (Slane et al, 2006;Walker et al, 2006). This downregulation appears to be very similar to complex II mutations in PGL/PH as a large majority of these tumours do not express a correctly assembled complex II (van Nederveen et al, 2009).…”

Section: Respiratory Chain Complexes and Apoptosismentioning

confidence: 86%

“…Other mutations of complex II subunits induce a decrease of the expression of their mRNA or their protein and lead to the depletion of the assembled complex II as revealed for a SDHB mutant in Drosophila (Walker et al, 2006) and for a SDHC mutant in hamster CCL16 B9 cells (Lemarie and Grimm, 2009). Both of these SDHB and SDHC mutants were associated with mild ROS production and with death or tumourigenesis, respectively (Slane et al, 2006;Walker et al, 2006).…”

Section: Respiratory Chain Complexes and Apoptosismentioning

confidence: 99%

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Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

2011

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Mutations in cancer cells affecting subunits of the respiratory chain (RC) indicate a central role of oxidative phosphorylation for tumourigenesis. Recent studies have suggested that such mutations of RC complexes impact apoptosis induction. We review here the evidence for this hypothesis, which in particular emerged from work on how complex I and II mediate signals for apoptosis. Both protein aggregates are specifically inhibited for apoptosis induction through different means by exploiting with protease activation and pH change, two widespread but independent features of dying cells. Nevertheless, both converge on forming reactive oxygen species for the demise of the cell. Investigations into these mitochondrial processes will remain a rewarding area for unravelling the causes of tumourigenesis and for discovering interference options.

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Section: Respiratory Chain Complexes and Apoptosismentioning

confidence: 86%

Section: Respiratory Chain Complexes and Apoptosismentioning

confidence: 99%

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

2011

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“…Next, we examined whether Parkin-mediated changes in dMfn levels were associated with altered mitochondrial morphology during aging. Drosophila adult flight muscle is an ideal system to study alterations in mitochondrial structure and function (44)(45)(46). In this tissue, we observed mitochondrial fragmentation (i.e., smaller and rounder mitochondria), as visualized by electron microscopy (EM), in young and aged Parkin-overexpressing flies (compare Fig.…”

Section: Parkin Overexpression Modulates Mitochondrial Dynamics and Amentioning

confidence: 90%

“…7. Standard procedure for EM analysis was carried out as described previously (44,45). See SI Materials and Methods for details.…”

Section: Methodsmentioning

confidence: 99%

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Rana

Rera

Walker

2013

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

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286

222

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Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Longlived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusionpromoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.energy metabolism | healthspan | mitophagy | neuronal aging | proteostasis A dvanced age is a major risk factor for many neurodegenerative disorders, including both Alzheimer's disease and Parkinson disease (PD), and yet the molecular mechanisms that link aging and neurodegeneration are poorly understood. To understand this connection, it is necessary to identify the molecular events and pathways that integrate aging and neurodegenerative disease. Several lines of evidence suggest that a decline in the ability to prevent and eliminate protein misfolding (1) and impaired mitochondrial function (2) are important factors in the increased risk of disease and death associated with aging. More specifically, although the correlation between neurodegenerative disease and protein aggregation in the brain has long been recognized (3), recent work in the nematode Caenorhabditis elegans (4-6) and the fruit fly Drosophila melanogaster (7) has shown that aging per se is associated with increased aggregation of a large number of proteins. At the same time, a decline in mitochondrial gene expression and/or energetic capacity is a hallmark of aging across diverse species (2, 8), whereas a failure to eliminate dysfunctional mitochondria has been implicated in the pathophysiology of a number of neurodegenerative diseases, including PD (9).The ubiquitin-proteasome system (UPS) is a critical component of the cellular pro...

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“…[ 35 S]methionine incorporation was also determined from isolated mitochondria (65). Briefly, labeled flies (five per sample) were gently crushed in a Dounce homogenizer [10 strokes with 0.4 mL of MIB buffer: 5 mM Tris, pH 7.4, 250 mM sucrose, 2 mM EGTA, and 0.3% (wt/vol) BSA].…”

Section: Methodsmentioning

confidence: 99%

The 4E-BP growth pathway regulates the effect of ambient temperature on Drosophila metabolism and lifespan

Carvalho

Drago

Hoxha

et al. 2017

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

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Changes in body temperature can profoundly affect survival. The dramatic longevity-enhancing effect of cold has long been known in organisms ranging from invertebrates to mammals, yet the underlying mechanisms have only recently begun to be uncovered. In the nematode Caenorhabditis elegans, this process is regulated by a thermosensitive membrane TRP channel and the DAF-16/FOXO transcription factor, but in more complex organisms the underpinnings of cold-induced longevity remain largely mysterious. We report that, in Drosophila melanogaster, variation in ambient temperature triggers metabolic changes in protein translation, mitochondrial protein synthesis, and posttranslational regulation of the translation repressor, 4E-BP (eukaryotic translation initiation factor 4E-binding protein). We show that 4E-BP determines Drosophila lifespan in the context of temperature changes, revealing a genetic mechanism for cold-induced longevity in this model organism. Our results suggest that the 4E-BP pathway, chiefly thought of as a nutrient sensor, may represent a master metabolic switch responding to diverse environmental factors.S tudies on the biological underpinnings of aging have uncovered numerous genetic and environmental factors regulating animal lifespan. Longevity-promoting genes include components of the insulin-like signaling pathway, the histone deacetylase Sir2, the GTPase Ras, TRP membrane channels, and transcription factors, among many others (1, 2). Environmental manipulations extending life include changes in nutrition (often referred to as caloric or dietary restriction), sexual/reproductive history, and ambient temperature (3-5).Of the factors known to impact aging, temperature is arguably the most promising. Lifespan extension by cold is evolutionarily conserved-documented in poikilotherms, such as worms and flies, and homeotherms, including mammals (4, 6-11)-and more robust than well-studied interventions such as dietary restriction (12, 13). However, the underlying mechanisms remain incompletely understood (10,14,15). In Caenorhabditis elegans, the effect of cold on survival involves the thermosensitive membrane channel TRPA-1 acting upstream of the DAF-16/FOXO transcription factor (14,15). This seminal finding countered the notion that longevity is the passive result of general thermodynamic changes, and favored instead the view that genetic pathways actively control lifespan in response to ambient temperature. However, these results have to date not been extended or replicated in other model organisms. Explanatory theories for the effect of cold on longevity include a reduction in reactive oxygen species generated by mitochondrial uncoupling proteins, suppression of autoimmune response, and changes in neuroendocrine factors (6,16,17), but these views remain largely speculative given the lack of further mechanistic insight into lifespan extension by cold in model organisms.We report that, in Drosophila, changes in temperature trigger a metabolic program impacting protein translation, mitochondrial prot...

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Hypersensitivity to oxygen and shortened lifespan in a Drosophila mitochondrial complex II mutant

Cited by 98 publications

References 27 publications

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

The 4E-BP growth pathway regulates the effect of ambient temperature on Drosophila metabolism and lifespan

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