Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction

Zhou, Xiaoshan; Mikaeloff, Flora; Curbo, Sophie; Zhao, Qian; Kuiper, Raoul V.; Végvári, Ákos; Neogi, Ujjwal; Karlsson, Anna

doi:10.1093/hmg/ddab168

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…Dguok F180S/F180S mice have not yet been systematically observed for the assessment of their life span. According to our preliminary observation, these animals survived up to 30 weeks without further apparent phenotypical or behavioral abnormalities, in line with the preliminary survival estimates of the murine Dguok KO mouse line (22,25). The differential mitochondrial DNA content in various tissues might play a role in the lean phenotype presented herein, and it seems, that the Dguok F180S/F180S mouse line also possesses su cient compensatory pathways ensuring su cient mitochondrial DNA levels, that do not further in uence their phenotypical appearance and survival.…”

Section: Discussionsupporting

confidence: 83%

“…The current mouse model has some phenotypic overlap with the previously described Dguok KO model, that is characterized by low body weight and decreased subcutaneous fat layer but also with liver damage (22). Furthermore, this mouse line also presents an altered expression of the enzymes of the Krebs cycle (25). Dguok F180S/F180S mice have not yet been systematically observed for the assessment of their life span.…”

Section: Discussionmentioning

confidence: 92%

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Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

et al. 2023

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Background Deoxyguanosine kinase (DGUOK) deficiency is one of the genetic causes of mitochondrial DNA depletion syndrome (MDDS) in humans, leading to the hepatocerebral or the isolated hepatic form of MDDS. Mouse models are helpful tools for the improvement of understanding of the pathophysiology of diseases and offer the opportunity to examine new therapeutic options. Methods Herein, we describe the generation and metabolic characterization of a mouse line carrying a homozygous DguokF180S/F180S mutation derived from an N-ethyl-N-nitrosourea-mutagenesis screen. Energy expenditure (EE), oxygen consumption (VO2) and carbon dioxide production (VCO2) were assessed in metabolic cages. LC-MS/MS was used to quantify plasma adrenal steroids. Plasma insulin and leptin levels were quantified with commercially available assay kits. Results Mutant animals displayed significantly lower body weights and reduced inguinal fat pad mass, in comparison to unaffected littermates. Biochemically, they were characterized by significantly lower blood glucose levels, accompanied by significantly lower insulin, total cholesterol, high density lipoprotein and triglyceride levels. They also displayed an almost 2-fold increase in transaminases. Moreover, absolute EE was comparable in mutant and control mice, but EE in mutants was uncoupled from their body weights. Histological examination of inguinal white adipose tissue (WAT) revealed adipocytes with multilocular fat droplets reminiscent of WAT browning. In addition, mRNA and protein expression of Ucp1 was increased. Mutant mice also presented differing mitochondrial DNA content in various tissues and altered metabolic activity in mitochondria, but no further phenotypical or behavioral abnormalities. Preliminary data imply normal survival of DguokF180S/F180S mutant animals. Conclusion Taken together, DGUOK mutation F180S leads to a lean phenotype, with lower glucose, insulin, and lipid levels rendering this mouse model not only useful for the study of MDDS forms but also for deciphering mechanisms resulting in a lean phenotype.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 92%

Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

et al. 2023

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“…Furthermore, fumarate upregulation in the 2-year sample suggests that the citric acid cycle (TCA Cycle), which is cardioprotective, is upregulated 56 (Figure 6B). Similarly, kynurenine, which is neuroprotective but also may play roles in energy production 57 , are upregulated (Figure 6B). The decreased presence of amino acids, such as serine, glutamate, and asparagine, in the aged samples, suggests that faster amino acid metabolism is occurring.…”

Section: Discussionmentioning

confidence: 95%

Three-Dimensional Mitochondria Reconstructions of Murine Cardiac Muscle Changes in Size Across Aging

Vue

Garza-López

Neikirk

et al. 2022

Preprint

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Cardiac disease remains a large cause of death among humans and therapies to treat it remain lacking. Mitochondria is heavily implicated in various critical functions of the cell not limited to the production of ATP. Critically, mitochondria break down across aging and heart also decrease in efficiency in aging. Key factors implicated in mitochondria morphology, such as the mitochondrial contact site and cristae organizing system (MICOS), role across aging remains to be seen in cardiac muscle. To better understand the relationship between mitochondria in heart, we used transmission electron microscopy (TEM) and serial block facing-scanning electron microscopy (SBF-SEM) to quantitatively analyze the 3D networks in cardiac muscle samples of mice at aging intervals. Cardiac muscle showed some breaking down across aging, decreased areas, increased mitochondria, but less fragmentation and wide-spread changes across 2-year aging than previous studies in skeletal muscle. In studying cristae, the inner folds of mitochondria, we observed a loss of morphology across aging. This mimicked what was observed upon CRISPR/Cas9 knockdown of mitofilin, Chchd3, Chchd6 and Opa-1 which showed increased lamellar cristae and fragmented mitochondria while mitochondria length and volume decreased. We are the first to examine mitochondria changes in cardiac muscle across aging. Notably, we noticed differences in skeletal muscle, which we have previously studied, and cardiac muscle that suggests a differential response to mitochondrial aging in cardiac and skeletal muscle. In combination, these data suggest that, in the heart, loss of the MICOS complex may be implicated in the loss of function in mitochondria that is seen across aging.

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“…DGUOK provides dAMP and dGMP for mtDNA replication. It has been shown that knockout of Dguok could lead to 95% reduction in mtDNA copy number in livers [ 9 ]. Therefore, our observation indicates liver has higher compensatory capacity to the deficiency in TK2 activity than in DGUOK activity.…”

Section: Discussionmentioning

confidence: 99%

Long term survival and abnormal liver fat accumulation in mice with specific thymidine kinase 2 deficiency in liver tissue

Zhao,

Zhou,

Yan

et al. 2023

PLoS ONE

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Deficiency in thymidine kinase 2 (TK2) causes mitochondrial DNA depletion. Liver mitochondria are severely affected in Tk2 complete knockout models and have been suggested to play a role in the pathogenesis of the Tk2 knockout phenotype, characterized by loss of hypodermal fat tissue, growth retardation and reduced life span. Here we report a liver specific Tk2 knockout (KO) model to further study mechanisms contributing to the phenotypic changes associated with Tk2 deficiency. Interestingly, the liver specific Tk2 KO mice had a normal life span despite a much lower mtDNA level in liver tissue. Mitochondrial DNA encoded peptide COXI did not differ between the Tk2 KO and control mice. However, the relative liver weight was significantly increased in the male Tk2 KO mouse model. Histology analysis indicated an increased lipid accumulation. We conclude that other enzyme activities can partly compensate Tk2 deficiency to maintain mtDNA at a low but stable level throughout the life span of the liver specific Tk2 KO mice. The lower level of mtDNA was sufficient for survival but led to an abnormal lipid accumulation in liver tissue.

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Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction

Cited by 5 publications

References 47 publications

Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

Three-Dimensional Mitochondria Reconstructions of Murine Cardiac Muscle Changes in Size Across Aging

Long term survival and abnormal liver fat accumulation in mice with specific thymidine kinase 2 deficiency in liver tissue

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