Mutations of mitochondrial DNA are not major contributors to aging of fruit flies

Kauppila, Timo E.S.; Bratić, Ana; Jensen, Martin Borch; Baggio, Francesca; Partridge, Linda; Jasper, Heinrich; Grönke, Sebastian; Larsson, Nils‐Göran

doi:10.1073/pnas.1721683115

Cited by 34 publications

(30 citation statements)

References 74 publications

(111 reference statements)

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“…To address the question if mtDNA mutations have an impact on ageing, a recent study engineered flies expressing a mutant version of the catalytic subunit of the mtDNA polymerase, thus introducing mtDNA mutations. Interestingly, in contrast with a previous study showing that even low levels of mtDNA mutations caused developmental delays in flies [60], mtDNA mutations did not broadly affect the lifespan or healthspan of adult flies [61].…”

Section: The Role Of Mitochondriacontrasting

confidence: 99%

Redox signalling and ageing: insights from Drosophila

Lennicke

Cochemé

2020

Biochemical Society Transactions

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Ageing and age-related diseases are major challenges for the social, economic and healthcare systems of our society. Amongst many theories, reactive oxygen species (ROS) have been implicated as a driver of the ageing process. As by-products of aerobic metabolism, ROS are able to randomly oxidise macromolecules, causing intracellular damage that accumulates over time and ultimately leads to dysfunction and cell death. However, the genetic overexpression of enzymes involved in the detoxification of ROS or treatment with antioxidants did not generally extend lifespan, prompting a re-evaluation of the causal role for ROS in ageing. More recently, ROS have emerged as key players in normal cellular signalling by oxidising redox-sensitive cysteine residues within proteins. Therefore, while high levels of ROS may be harmful and induce oxidative stress, low levels of ROS may actually be beneficial as mediators of redox signalling. In this context, enhancing ROS production in model organisms can extend lifespan, with biological effects dependent on the site, levels, and specific species of ROS. In this review, we examine the role of ROS in ageing, with a particular focus on the importance of the fruit fly Drosophila as a powerful model system to study redox processes in vivo.

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Section: The Role Of Mitochondriacontrasting

confidence: 99%

Redox signalling and ageing: insights from Drosophila

Lennicke

Cochemé

2020

Biochemical Society Transactions

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“…Given that our mutator transgene appears to express endogenous levels of PolG transcript, we are at a loss to explain this discrepancy. Moreover, heterozygotes for the PolG knock-in allele displayed no obvious effect on lifespan [41], whereas our mutator lines displayed a dose dependent decrease in lifespan. The explanation for this difference is also unknown but may reflect differences in the mtDNA genetic background in these two studies, which we have found in unpublished work can influence lifespan.…”

Section: Discussionmentioning

confidence: 99%

Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ

et al. 2018

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Mitochondrial DNA (mtDNA) mutations cause severe maternally inherited syndromes and the accumulation of somatic mtDNA mutations is implicated in aging and common diseases. However, the mechanisms that influence the frequency and pathogenicity of mtDNA mutations are poorly understood. To address this matter, we created a Drosophila mtDNA mutator strain expressing a proofreading-deficient form of the mitochondrial DNA polymerase. Mutator flies have a dramatically increased somatic mtDNA mutation frequency that correlates with the dosage of the proofreading-deficient polymerase. Mutator flies also exhibit mitochondrial dysfunction, shortened lifespan, a progressive locomotor deficit, and loss of dopaminergic neurons. Surprisingly, the frequency of nonsynonymous, pathogenic, and conserved-site mutations in mutator flies exceeded predictions of a neutral mutational model, indicating the existence of a positive selection mechanism that favors deleterious mtDNA variants. We propose from these findings that deleterious mtDNA mutations are overrepresented because they selectively evade quality control surveillance or because they are amplified through compensatory mitochondrial biogenesis.

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“…The experimentally obtained very high mtDNA mutation levels, which are unlikely to be found in nature, also reduce the lifespan of fruit flies. Additionally, adulthood is less sensitive to mtDNA mutations than is embryonic development …”

Section: Mitochondrial Anomalies With Agingmentioning

confidence: 99%

Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure

et al. 2019

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Summary Mitochondria not only supply the energy for cell function, but also take part in cell signaling. This review describes the dysfunctions of mitochondria in aging and neurodegenerative diseases, and the signaling pathways leading to mitochondrial biogenesis (including PGC‐1 family proteins, SIRT1, AMPK) and mitophagy (parkin‐Pink1 pathway). Understanding the regulation of these mitochondrial pathways may be beneficial in finding pharmacological approaches or lifestyle changes (caloric restrict or exercise) to modulate mitochondrial biogenesis and/or to activate mitophagy for the removal of damaged mitochondria, thus reducing the onset and/or severity of neurodegenerative diseases.

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Mutations of mitochondrial DNA are not major contributors to aging of fruit flies

Cited by 34 publications

References 74 publications

Redox signalling and ageing: insights from Drosophila

Redox signalling and ageing: insights from Drosophila

Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ

Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure

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