Crif1 Deficiency Reduces Adipose OXPHOS Capacity and Triggers Inflammation and Insulin Resistance in Mice

Ryu, Min Jeong; Kim, Soung Jung; Kim, Yong Kyung; Choi, Min Jeong; Tadi, Surendar; Lee, Min Hee; Lee, Seong Eun; Chung, Hyo Kyun; Jung, Saet Byel; Kim, Hyun‐Jin; Jo, Young Suk; Kim, Koon Soon; Lee, Sang‐Hee; Kim, Jin Man; Kweon, Gi Ryang; Park, Ki Cheol; Lee, Jung Uee; Kong, Young Yun; Lee, Chul‐Ho; Chung, Jongkyeong; Shong, Minho

doi:10.1371/journal.pgen.1003356

Cited by 56 publications

(65 citation statements)

References 61 publications

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“…These findings supported the hypothesis that skeletal muscle mitochondrial deficiency does not mediate insulin resistance [25]. Collectively, although these gene manipulation studies revealed rather universal results, they require attention during interpretation because they casually reflect extreme cases that might lead to the activation of other compensatory mechanisms.…”

Section: Relationship Between Mitochondrial Function and Insulin Resisupporting

confidence: 74%

The relationship between muscle mitochondrial nutritional overloading and insulin resistance

Jeon

Moon

Won

et al. 2017

Yeungnam Univ J Med

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The incidence of type 2 diabetes mellitus and insulin resistance is growing rapidly. Multiple organs including the liver, skeletal muscle and adipose tissue control insulin sensitivity coordinately, but the mechanism of skeletal muscle insulin resistance has not yet been fully elucidated. However, there is a growing body of evidence that lipotoxicity induced by mitochondrial dysfunction in skeletal muscle is an important mediator of insulin resistance. However, some recent findings suggest that skeletal mitochondrial dysfunction generated by genetic manipulation is not always correlated with insulin resistance in animal models. A high fat diet can provoke insulin resistance despite a coordinate increase in skeletal muscle mitochondria, which implies that mitochondrial dysfunction is not mandatory in insulin resistance. Furthermore, incomplete fatty acid oxidation by excessive nutrition supply compared to mitochondrial demand can induce insulin resistance without preceding impairment of mitochondrial function. Taken together we suggested that skeletal muscle mitochondrial overloading, not mitochondrial dysfunction, plays a pivotal role in insulin resistance.

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Section: Relationship Between Mitochondrial Function and Insulin Resisupporting

confidence: 74%

The relationship between muscle mitochondrial nutritional overloading and insulin resistance

Jeon

Moon

Won

et al. 2017

Yeungnam Univ J Med

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“…Numbers under the lanes are esi-2.1 levels normalized to luc knockdown. (F) S2 cells were treated with dsRNAs targeting luciferase (luc; negative control), Dcr-2, and dCRIF, respectively, and then the cell lysates were incubated with p 32 , dCRIF EY03252 heterozygous flies of the same age were infected with DCV and the viral load was quantified by qPCR amplification of viral RNA. The rp49 gene was used as a control.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, many different functions have been reported for mammalian CRIF1, including functions as a transcription co-factor and functions in mitochondria. [29][30][31][32][33] We are currently investigating the functions of dCRIF and its role in Dcr-2 stability.…”

Section: Discussionmentioning

confidence: 99%

Requirement for CRIF1 in RNA interference and Dicer-2 stability

et al. 2014

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Abbreviations: CRIF1, Cytokine response 6 (CR6)-interacting factor 1; Gadd45GIP1, growth arrest and DNA-damageinducible 45-gamma interacting protein 1; Dcr-2, RNAase III enzyme Dicer-2 RNA interference (RNAi) is a eukaryotic gene-silencing system. Although the biochemistry of RNAi is relatively well defined, how this pathway is regulated remains incompletely understood. To identify genes involved in regulating the RNAi pathway, we screened for genetic mutations in Drosophila that alter the efficiency of RNAi. We identified the Drosophila homolog of the mammalian CR6-interacting factor 1 (CRIF1), also known as growth arrest and DNA-damageinducible 45-gamma interacting protein (Gadd45GIP1), as a potential new regulator of the RNAi pathway. Loss-offunction mutants of Drosophila CRIF1 (dCRIF) are deficient in RNAi-mediated target gene knock-down, in the biogenesis of small interfering RNA (siRNA) molecules, and in antiviral immunity. Moreover, we show that dCRIF may function by interacting with, and stabilizing, the RNase III enzyme Dicer-2. Our results suggest that dCRIF may play an important role in regulating the RNAi pathway.

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“…As the variations in our mini-pig model were mainly restricted to highrespiratory tissues (brain, diaphragm, muscle, liver, heart, and fat), this suggests that there is epigenetic regulation of variant load to ensure the regulation of OXPHOS performance, which is reflected by higher mtDNA copy number (Kelly et al 2012;St John 2014). For example, for adipose tissue, this would link OXPHOS regulation to adipogenesis (Hofmann et al 2012), insulin metabolism (Ryu et al 2013), and thermogenesis (Duteil et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

et al. 2016

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The maternally inherited mitochondrial genome (mtDNA) is present in multimeric form within cells and harbors sequence variants (heteroplasmy). While a single mtDNA variant at high load can cause disease, naturally occurring variants likely persist at low levels across generations of healthy populations. To determine how naturally occurring variants are segregated and transmitted, we generated a mini-pig model, which originates from the same maternal ancestor. Following next-generation sequencing, we identified a series of low-level mtDNA variants in blood samples from the female founder and her daughters. Four variants, ranging from 3% to 20%, were selected for validation by high-resolution melting analysis in 12 tissues from 31 animals across three generations. All four variants were maintained in the offspring, but variant load fluctuated significantly across the generations in several tissues, with sexspecific differences in heart and liver. Moreover, variant load was persistently reduced in high-respiratory organs (heart, brain, diaphragm, and muscle), which correlated significantly with higher mtDNA copy number. However, oocytes showed increased heterogeneity in variant load, which correlated with increased mtDNA copy number during in vitro maturation. Altogether, these outcomes show that naturally occurring mtDNA variants segregate and are maintained in a tissue-specific manner across generations. This segregation likely involves the maintenance of selective mtDNA variants during organogenesis, which can be differentially regulated in oocytes and preimplantation embryos during maturation.KEYWORDS mitochondrial DNA; segregation; variants; generations; embryo W HILE the nuclear genome is inherited from both parents, the mitochondrial genome (mtDNA) is only inherited from the population present in the oocyte at fertilization (Chinnery et al. 2000). The porcine mitochondrial genome is 16.7 kb in size and encodes 13 of the subunits of the electron transport chain, which drives ATP synthesis through the biochemical process of oxidative phosphorylation (OXPHOS) (Ursing and Arnason 1998). It also encodes 22 transfer RNAs (tRNAs), which are interspersed between the encoding genes, and 2 ribosomal RNA (rRNA) complexes. mtDNA is located in the mitochondrial matrix and is tethered to proteins, which collectively form the mitochondrial nucleoid (Kucej and Butow 2007). mtDNA is present in multiple copies within cells and these genomes can be polymorphic. Consequently, cells can inherently harbor variant and wild-type (WT) sequences, i.e., heteroplasmic populations, of mtDNA at different frequencies (Wallace and Chalkia 2013).Most mtDNA variants are nonpathogenic (Ramos et al. 2013) but specific nucleotide mutations and large-scale deletions can lead to molecular defects, resulting in a wide range of clinical conditions, known as mitochondrial diseases (McFarland et al. 2007). Within the spectrum of mitochondrial diseases, the onset of symptoms can vary according to Copyright © 2016 Apart from the occurrence o...

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Crif1 Deficiency Reduces Adipose OXPHOS Capacity and Triggers Inflammation and Insulin Resistance in Mice

Cited by 56 publications

References 61 publications

The relationship between muscle mitochondrial nutritional overloading and insulin resistance

The relationship between muscle mitochondrial nutritional overloading and insulin resistance

Requirement for CRIF1 in RNA interference and Dicer-2 stability

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

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