Aging impact on biochemical activities and gene expression of Drosophila melanogaster mitochondria

Dubessay, Pascal; Garreau-Balandier, Isabelle; Jarrousse, Anne-Sophie; Fleuriet, Annie; Sion, Benoı̂t; Debise, Roger; Alziari, Serge

doi:10.1016/j.biochi.2007.03.018

Cited by 26 publications

(29 citation statements)

References 60 publications

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“…The production of ATP in mitochondria declines with age during the human aging process [40]. This also holds true for Drosophila [41]. Therefore, a decline in mitochondrial function due to an increase in ROS production may limit an organism's lifespan.…”

Section: Discussionmentioning

confidence: 87%

Role of Drosophila alkaline ceramidase (Dacer) in Drosophila development and longevity

Yang

Zhou

Yuan

et al. 2010

Cell. Mol. Life Sci.

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Ceramidases catalyze the hydrolysis of ceramides to generate sphingosine (SPH) and fatty acids, and ceramide metabolism is implicated in various biological responses in Drosophila melanogaster. Here we report the cloning, biochemical characterization, and functional analysis of a Drosophila alkaline ceramidase (Dacer). Dacer, a membrane-bound protein of 284 amino acids, shares homology with yeast and mammalian alkaline ceramidases. Overexpression of Dacer in High Five insect cells increases ceramidase activity in the alkaline pH range, indicating that Dacer is a bona fide alkaline ceramidase. Dacer mRNA is highly expressed in the midgut and at the pupal stage. An inactivation of Dacer by insertional mutagenesis increases the levels of ceramides in both Drosophila pupae and adult flies. Dacer inactivation increases Drosophila pre-adult development time, lifespan, and anti-oxidative stress capacity. Collectively, these results suggest that Dacer plays an important role in the Drosophila development and longevity by controlling the metabolism of ceramides.

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Section: Discussionmentioning

confidence: 87%

Role of Drosophila alkaline ceramidase (Dacer) in Drosophila development and longevity

Yang

Zhou

Yuan

et al. 2010

Cell. Mol. Life Sci.

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“…Microarray studies have shown an age-related decrease in the expression of genes involved in metabolism and respiratory chain function in tissues such as heart, skeletal muscle and brain (28–31). Observations made in hearts of senescent rats and flies show a reduced rate of mitochondrial transcription without affecting mtDNA copy number (32,33). Also, reduced 12S rRNA and COX1 transcript levels were found in hearts, cerebral hemispheres and cerebellum, but not in the liver, of senescent rats (34).…”

Section: Discussionmentioning

confidence: 99%

Maintenance of respiratory chain function in mouse hearts with severely impaired mtDNA transcription

Freyer

Park

Ekstrand

et al. 2010

Nucleic Acids Research

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The basal mitochondrial transcription machinery is essential for biogenesis of the respiratory chain and consists of mitochondrial RNA polymerase, mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2. This triad of proteins is sufficient and necessary for mtDNA transcription initiation. Abolished mtDNA transcription caused by tissue-specific knockout of TFAM in the mouse heart leads to early onset of a severe mitochondrial cardiomyopathy with lethality within the first post-natal weeks. Here, we describe a mouse model expressing human TFAM instead of the endogenous mouse TFAM in heart. These rescue mice have severe reduction in mtDNA transcription initiation, but, surprisingly, are healthy at the age of 52 weeks with near-normal steady-state levels of transcripts. In addition, we demonstrate that heavy-strand mtDNA transcription normally terminates at the termination-associated sequence in the control region. This termination is abolished in rescue animals resulting in heavy (H)-strand transcription of the entire control region. In conclusion, we demonstrate here the existence of an unexpected mtDNA transcript stabilization mechanism that almost completely compensates for the severely reduced transcription initiation in rescue hearts. Future elucidation of the underlying molecular mechanism may provide a novel pathway to treat mitochondrial dysfunction in human pathology.

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“…Our findings of a positive effect on reduction of oxidative damage with an earlier decrease in ETC activity in Indy long-lived flies supports the hypothesis that the decrease in ETC activity during normal aging may be a compensatory response rather than a passive deleterious consequence of aging. During aging, an increasing burden of mitochondrial ROS generation may trigger a decrease in ETC activity (27,28) leading to a decrease in mitochondrial ROS production and delay in accumulation of oxidative damage. In the Indy long-lived mutant, the decrease in ETC activity and mitochondrial ROS production is initiated earlier and may contribute to the life span extension seen in Indy flies.…”

Section: Discussionmentioning

confidence: 99%

Long-lived Indy induces reduced mitochondrial reactive oxygen species production and oxidative damage

Neretti

Wang²,

Brodsky³

et al. 2009

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

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Decreased Indy activity extends lifespan in D. melanogaster without significant reduction in fecundity, metabolic rate, or locomotion. To understand the underlying mechanisms leading to lifespan extension in this mutant strain, we compared the genome-wide gene expression changes in the head and thorax of adult Indy mutant with control flies over the course of their lifespan. A signature enrichment analysis of metabolic and signaling pathways revealed that expression levels of genes in the oxidative phosphorylation pathway are significantly lower in Indy starting at day 20. We confirmed experimentally that complexes I and III of the electron transport chain have lower enzyme activity in Indy longlived flies by Day 20 and predicted that reactive oxygen species (ROS) production in mitochondria could be reduced. Consistently, we found that both ROS production and protein damage are reduced in Indy with respect to control. However, we did not detect significant differences in total ATP, a phenotype that could be explained by our finding of a higher mitochondrial density in Indy mutants. Thus, one potential mechanism by which Indy mutants extend life span could be through an alteration in mitochondrial physiology leading to an increased efficiency in the ATP/ROS ratio.electron transport chain ͉ mitochondria ͉ oxidative phosphorylation ͉ Drosophila ͉ aging U nderstanding the biological and physiological underpinnings of aging and the development of interventions to ameliorate its deleterious effects has been the subject of much interest. Identification and examination of specific genetic alterations that extend life span is one common approach for uncovering mechanisms underlying normal aging. A number of single gene alterations that extend healthy life span in model organisms have been isolated, but delineating the specific physiological changes responsible for their life span extending effects has been challenging (1).High throughput genomic analyses have emerged as an unbiased method for providing information of the physiological changes involved in mediating complex biological phenomena such as longevity. In particular, whole genome transcriptional studies (microarrays) to identify specific genes or physiological systems important in longevity determination have been successfully used in both nematodes and flies. Microarray studies of daf-2 long-lived nematodes identified specific genes that were then functionally verified as causally related to the daf-2 life span extension (2).Restricting the examination of microarrays to only those genes identically shared between different interventions may limit the ability to detect some of the physiologically relevant changes important in complex biological phenomena such as life span extension. As more data becomes available from high throughput gene expression studies, analyses have shifted from a gene centric model to a pathway centric approach. It has been realized that reproducibility of experiments, and comparison across interventions that should have resulted in simil...

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Aging impact on biochemical activities and gene expression of Drosophila melanogaster mitochondria

Cited by 26 publications

References 60 publications

Role of Drosophila alkaline ceramidase (Dacer) in Drosophila development and longevity

Role of Drosophila alkaline ceramidase (Dacer) in Drosophila development and longevity

Maintenance of respiratory chain function in mouse hearts with severely impaired mtDNA transcription

Long-lived Indy induces reduced mitochondrial reactive oxygen species production and oxidative damage

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