Inactivation of Pif1 helicase causes a mitochondrial myopathy in mice

Bannwarth, Sylvie; Berg-Alonso, Laetitia; Augé, Gaëlle; Fragaki, Konstantina; Kolesar, Jill E.; Lespinasse, Françoise; Lacas‐Gervais, Sandra; Burel‐Vandenbos, Fanny; Villa, Elodie; Belmonte, Frances; Michiels, Jean‐François; Ricci, Jean-Ehrland; Gherardi, Romain K.; Harrington, Lea; Kaufman, Brett A.; Paquis‐Flucklinger, Véronique

doi:10.1016/j.mito.2016.02.005

Cited by 35 publications

(36 citation statements)

References 47 publications

(65 reference statements)

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“…Despite the presence of mtDNA deletions, Deletor mice do not display decreased physical performance or increased body weight [35]. These results from the Deletor mice suggest that the mtDNA deletions in the skeletal muscle of PIF1 KO mice previously described [4] do not contribute to the decreased activity and increased body weight shown in the current study.…”

Section: The Dissociation Between Obesity and Metabolic Dysfunction Isupporting

confidence: 59%

“…Wild type C57BL/6J mice were from the Jackson Laboratory (Bar Harbor, ME). PIF1 KO mice were originally developed in the C57BL/6 background [4,12], but the Pif1 deletion was maintained in the C57BL/6J background exclusively for more than 10 generations. Animals were fed normal or WD chow ad libitum and housed in a 12 h light to dark cycling room.…”

Section: Animalsmentioning

confidence: 99%

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Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance

Kaufman

Belmonte

Dedousis

et al. 2018

Preprint

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Petite Integration Factor 1 (PIF1) is a multifunctional helicase present in nuclei and mitochondria. PIF1 knock out (KO) mice exhibit accelerated weight gain and decreased wheel running on a normal chow diet. In the current study, we investigated whether Pif1 removal alters whole body metabolism in response to weight gain. PIF1 KO and wild type (WT) C57BL/6J mice were fed a Western diet (WD) rich in fat and carbohydrates before evaluation of their metabolic phenotype. Compared with weight gain-resistant WT female mice, WD-fed PIF1 KO females, but not males, showed accelerated adipose deposition, decreased locomotor activity, and reduced whole-body energy expenditure without increased dietary intake. Surprisingly, PIF1 KO females were protected against obesity-induced alterations in fasting blood glucose and glucose clearance. WDfed PIF1 KO females developed mild hepatic steatosis and associated changes in liver gene expression that were absent in weight-matched, WD-fed female controls, linking hepatic steatosis to Pif1 ablation rather than increased body weight. WD-fed PIF1 KO females also showed decreased gene expression of inflammatory markers in adipose tissue. Collectively, these data separated weight gain from inflammation and impaired glucose homeostasis. They also support a role for Pif1 in weight gain resistance and liver metabolic dysregulation during nutrient stress.

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Section: The Dissociation Between Obesity and Metabolic Dysfunction Isupporting

confidence: 59%

Section: Animalsmentioning

confidence: 99%

Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance

Kaufman

Belmonte

Dedousis

et al. 2018

Preprint

Self Cite

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“…Recent studies have shown Twinkle helicase to be essential for mtDNA replication, as depletion of Twinkle causes severe mtDNA depletion (10). Pif1 is another helicase that has also been shown to cause mitochondrial instability: depletion of Pif1 causes deficiency in repairing oxidative stress-induced mtDNA damage and mitochondrial myopathy (11). POLG is crucial as it is the only replicative, highly-processive polymerase in the mitochondria, and also is necessary in the repair of mtDNA (12).…”

Section: Mtdna In Mitochondrial Bioenergetics and Biogenesismentioning

confidence: 99%

The little big genome the organization of mitochondrial DNA

Garcia¹,

Jones²,

Ramos

et al. 2017

Front Biosci

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The small (16,569 base pair) human mitochondrial genome plays a significant role in cell metabolism and homeostasis. Mitochondrial DNA (mtDNA) contributes to the generation of complexes which are essential to oxidative phosphorylation (OXPHOS). As such, mtDNA is directly integrated into mitochondrial biogenesis and signaling and regulates mitochondrial metabolism in concert with nuclear-encoded mitochondrial factors. Mitochondria are a highly dynamic, pleiomorphic network that undergoes fission and fusion events. Within this network, mtDNAs are packaged into structures called nucleoids which are actively distributed in discrete foci within the network. This sensitive organelle is frequently disrupted by insults such as oxidants and inflammatory cytokines, and undergoes genomic damage with double- and single-strand breaks that impair its function. Collectively, mtDNA is emerging as a highly sensitive indicator of cellular stress, which is directly integrated into the mitochondrial network as a contributor of a wide range of critical signaling pathways.

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“…Mice lacking PIF1 show a mitochondrial myopathy, suggesting a subtle role in mtDNA maintenance (BANNWARTH et al 2016). The expression of mouse and human PIF1 is limited to highly proliferating embryonic stem cells and peaks in late S/G2 phase, consistent with a role in DNA replication (MATEYAK AND ZAKIAN 2006).…”

Section: Introductionmentioning

confidence: 95%

TheDrosophila melanogasterPIF1 helicase promotes survival during replication stress and processive DNA synthesis during double-strand gap repair

Kocak

Dykstra

Németh

et al. 2019

Preprint

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PIF1 is a 5' to 3' DNA helicase that can unwind double-stranded DNA and disrupt nucleic acidprotein complexes. In Saccharomyces cerevisiae, Pif1 plays important roles in mitochondrial and nuclear genome maintenance, telomere length regulation, unwinding of G-quadruplex structures, and DNA synthesis during break-induced replication. Some, but not all, of these functions are shared with other eukaryotes. To gain insight into the evolutionarily conserved functions of PIF1, we created pif1 null mutants in Drosophila melanogaster and assessed their phenotypes throughout development. We found that pif1 mutant larvae exposed to high concentrations of hydroxyurea, but not other DNA damaging agents, experience reduced survival to adulthood.Embryos lacking PIF1 fail to segregate their chromosomes efficiently during early nuclear divisions, consistent with a defect in DNA replication. Furthermore, loss of the BRCA2 protein, which is required for homologous recombination and stabilization of stalled replication forks in metazoans, causes synthetic lethality in third instar larvae lacking either PIF1 or the polymerase delta subunit POL32. Interestingly, pif1 mutants have a reduced ability to synthesize DNA during repair of a double-stranded gap, but only in the absence of POL32. Together, these results support a model in which Drosophila PIF1 functions to promote efficient DNA synthesis during times of replication stress and acts independently of POL32 to promote synthesis during doublestrand gap repair.

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Inactivation of Pif1 helicase causes a mitochondrial myopathy in mice

Cited by 35 publications

References 47 publications

Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance

Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance

The little big genome the organization of mitochondrial DNA

TheDrosophila melanogasterPIF1 helicase promotes survival during replication stress and processive DNA synthesis during double-strand gap repair

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