Abstract:Mitochondria have been increasingly recognized as a central regulatory nexus for multiple metabolic pathways, in addition to ATP production via oxidative phosphorylation (OXPHOS). Here we show that inducing mitochondrial DNA (mtDNA) stress in Drosophila using a mitochondrially-targeted Type I restriction endonuclease (mtEcoBI) results in unexpected metabolic reprogramming in adult flies, distinct from effects on OXPHOS. Carbohydrate utilization was repressed, with catabolism shifted towards lipid oxidation, ac… Show more
“…It is noteworthy that during the course of preparing this manuscript, a similar study on the effect of mtDNA manipulation on embryonic development and metabolism in fruit fly was reported [43]. In the Drosophila model, reduction of zygote mtDNA copy number using a mitochondrially targeted endonuclease was shown to effectively perturb embryonic development, as we have seen in mice.…”
Adverse fetal environment, in particular a shortage or excess of nutrients, is associated with increased risks of metabolic diseases later in life. However, the molecular mechanisms underlying this developmental origin of adult diseases remain unclear. Here, we directly tested the role of mitochondrial stress in mediating fetal programming in mice by enzymatically depleting mtDNA in zygotes. mtDNA‐targeted plasmid microinjection is used to reduce embryonic mtDNA copy number directly, followed by embryo transfer. Mice with reduced zygote mtDNA copy number were born morphologically normal and showed no accelerated body weight gain. However, at 5 months of age these mice showed markedly increased hepatic lipidosis and became glucose‐intolerant. Hepatic mRNA and protein expressions of peroxisome proliferator‐activated receptor α (Pparα), a key transcriptional regulator of lipid metabolism, were significantly decreased as a result of increased DNA methylation in its proximal regulatory region. These results indicate that perturbation of mitochondrial function around the periconceptional period causes hypermethylation and thus suppressed expression of PPARα in fetal liver, leading to impaired hepatic lipid metabolism. Our findings provide the first direct evidence that mitochondrial stress mediates epigenetic changes associated with fetal programming of adult diseases in a mammalian system.
“…It is noteworthy that during the course of preparing this manuscript, a similar study on the effect of mtDNA manipulation on embryonic development and metabolism in fruit fly was reported [43]. In the Drosophila model, reduction of zygote mtDNA copy number using a mitochondrially targeted endonuclease was shown to effectively perturb embryonic development, as we have seen in mice.…”
Adverse fetal environment, in particular a shortage or excess of nutrients, is associated with increased risks of metabolic diseases later in life. However, the molecular mechanisms underlying this developmental origin of adult diseases remain unclear. Here, we directly tested the role of mitochondrial stress in mediating fetal programming in mice by enzymatically depleting mtDNA in zygotes. mtDNA‐targeted plasmid microinjection is used to reduce embryonic mtDNA copy number directly, followed by embryo transfer. Mice with reduced zygote mtDNA copy number were born morphologically normal and showed no accelerated body weight gain. However, at 5 months of age these mice showed markedly increased hepatic lipidosis and became glucose‐intolerant. Hepatic mRNA and protein expressions of peroxisome proliferator‐activated receptor α (Pparα), a key transcriptional regulator of lipid metabolism, were significantly decreased as a result of increased DNA methylation in its proximal regulatory region. These results indicate that perturbation of mitochondrial function around the periconceptional period causes hypermethylation and thus suppressed expression of PPARα in fetal liver, leading to impaired hepatic lipid metabolism. Our findings provide the first direct evidence that mitochondrial stress mediates epigenetic changes associated with fetal programming of adult diseases in a mammalian system.
“…This indicates reduced glucose transport, depriving glycolysis of its substrate and decreasing its end-product pyruvate ( n = 4, figure 2 b ). Administering metformin, an anti-diabetic drug that facilitates glucose uptake in both humans and flies [ 32 , 33 ], restored the normal balance in the flies' carbohydrate/lipid usage ( n = 10) and increased their RER ( n = 20) to normal value ( figure 2 c ). Figure 2 Effects of predator stress on metabolism/behaviour and pharmacological complementation in flies reared with spiders (predators) or without (control) spiders.…”
Predation can have both lethal and non-lethal effects on prey. The non-lethal effects of predation can instil changes in prey life history, behaviour, morphology and physiology, causing adaptive evolution. The chronic stress caused by sustained predation on prey is comparable to chronic stress conditions in humans. Conditions like anxiety, depression, and post-traumatic stress syndrome have also been implicated in the development of metabolic disorders such as obesity and diabetes. In this study, we found that predator stress induced during larval development in fruit flies
Drosophila melanogaster
impairs carbohydrate metabolism by systemic inhibition of Akt protein kinase, which is a central regulator of glucose uptake. However,
Drosophila
grown with predators survived better under direct spider predation in the adult phase. Administration of metformin and 5-hydroxytryptophan (5-HTP), a precursor of the neurotransmitter serotonin, reversed these effects. Our results demonstrate a direct link between predator stress and metabolic impairment, suggesting that a diabetes-like biochemical phenotype may be adaptive in terms of survival and reproductive success. We provide a novel animal model to explore the mechanisms responsible for the onset of these metabolic disorders, which are highly prevalent in human populations.
“…Finally, in a different study ( Bahhir et al., 2019 ), stress imposed upon mtDNA by the ubiquitous expression of a bacterial type I restriction endonuclease produced a range of metabolic abnormalities unrelated to OXPHOS, including decreased levels of dopamine, and accompanying behavioral changes, notably in feeding. Dietary supplementation with L-DOPA restored wild-type feeding behavior and delayed the onset of lethality in the model.…”
Summary
Dopaminergic (DA) neurons have been implicated as key targets in neurological disorders, notably those involving locomotor impairment, and are considered to be highly vulnerable to mitochondrial dysfunction, a common feature of such diseases. Here we investigated a
Drosophila
model of locomotor disorders in which functional impairment is brought about by pan-neuronal RNAi knockdown of subunit COX7A of cytochrome oxidase (COX). Despite minimal neuronal loss by apoptosis, the expression and activity of tyrosine hydroxylase was decreased by half. Surprisingly, COX7A knockdown specifically targeted to DA neurons did not produce locomotor defect. Instead, using various drivers, we found that COX7A knockdown in specific groups of cholinergic and glutamatergic neurons underlay the phenotype. Based on our main finding, the vulnerability of DA neurons to mitochondrial dysfunction as a cause of impaired locomotion in other organisms, including mammals, warrants detailed investigation.
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