Age‐induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge

Moore, Timothy M.; Zhou, Zhenqi; Strumwasser, Alexander R.; Cohn, Whitaker; Lin, Athena W.; Cory, Kevin; Whitney, Kate; Ho, Theodore; Ho, Tammy Szu-Yu; Lee, Joseph L.; Rucker, Daniel H.; Hoang, Austin; Widjaja, Kevin; Abrishami, Aaron; Charugundla, Sarada; Stiles, Linsey; Whitelegge, Julian P.; Turcotte, Lorraine P.; Wanagat, Jonathan; Hevener, Andrea L.

doi:10.1111/acel.13166

Cited by 6 publications

(5 citation statements)

References 73 publications

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“…Interestingly, there were gender‐specific differences for heart and liver tissues for one variant and generational differences for several tissues for the same variant (G. Cagnone et al, 2016 ). Indeed, the consensus opinion is that mtDNA point mutations associated with mammalian aging are insufficient to cause a phenotypic response (Moore et al, 2020 ). For example, in hair, the exponential increase in mutation with age ranges from 0 to 1.436 ± 0.2086% of total mtDNA content (Zheng et al, 2012 ), which, in the context of mtDNA copy number per cell suggests little if no impact on health and well‐being.…”

Section: The Mitochondrial Genetic Bottleneckmentioning

confidence: 99%

The role of mtDNA in oocyte quality and embryo development

John

Okada

Andreas

et al. 2022

Molecular Reproduction Devel

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The mitochondrial genome resides in the mitochondria present in nearly all cell types. The porcine (Sus scrofa) mitochondrial genome is circa 16.7 kb in size and exists in the multimeric format in cells. Individual cell types have different numbers of mitochondrial DNA (mtDNA) copy number based on their requirements for ATP produced by oxidative phosphorylation. The oocyte has the largest number of mtDNA of any cell type. During oogenesis, the oocyte sets mtDNA copy number in order that sufficient copies are available to support subsequent developmental events. It also initiates a program of epigenetic patterning that regulates, for example, DNA methylation levels of the nuclear genome. Once fertilized, the nuclear and mitochondrial genomes establish synchrony to ensure that the embryo and fetus can complete each developmental milestone. However, altering the oocyte's mtDNA copy number by mitochondrial supplementation can affect the programming and gene expression profiles of the developing embryo and, in oocytes deficient of mtDNA, it appears to have a positive impact on the embryo development rates and gene expression profiles. Furthermore, mtDNA haplotypes, which define common maternal origins, appear to affect developmental outcomes and certain reproductive traits. Nevertheless, the manipulation of the mitochondrial content of an oocyte might have a developmental advantage.

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Section: The Mitochondrial Genetic Bottleneckmentioning

confidence: 99%

The role of mtDNA in oocyte quality and embryo development

John

Okada

Andreas

et al. 2022

Molecular Reproduction Devel

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“…They found heterozygous mice had some difference at the molecular level compared with WT mice, but there was no difference in phenotype or life span between heterozygous and WT mice. However, homozygous mice all showed significant pathology damage in mitochondria dysfunction and phenotypes [13,34]. For example, D257A mutant of PolG directed reduced the content of electron transport chain (ETC) complexes I, III and IV which could promote skeletal muscle apoptosis and sarcopenia [35], and Tadafumi et.al constructed same model in PolG +/D257A mice which were recognized had no difference in phenotypes of WT mice [36,37], while they found the motor dysfunction caused by heterozygous mutation PolG was significant milder than that in homozygous mutation mice [38].…”

Section: Discussionmentioning

confidence: 97%

“…PolG D257A mutation mice was constructed as a mitochondria damaged model which the point mutation located in the proof-reading-deficient version of PolG and damaged 3'-5' exonuclease activity of polymerase, resulting in 3-fold to 5-fold increment of mutant mtDNA and increased amounts of deleted mtDNA [1]. Some research also revealed PolG deficiency brought alteration to cellular Ivyspring International Publisher metabolism [12,13]. Thus, PolG was recognized as a crucial stabilization factor of mitochondria, and any deficiency of PolG could damage mitochondrial function and eventually lead to cellular senescence induced by mitochondria.…”

Section: Introductionmentioning

confidence: 99%

DNA Polymerase Gamma Recovers Mitochondrial Function and Inhibits Vascular Calcification by Interacted with p53

Wang¹,

Wu²,

You³

et al. 2022

Int. J. Biol. Sci.

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DNA polymerase gamma (PolG) is the major polymerase of mitochondrial DNA (mtDNA) and essential for stabilizing mitochondrial function. Vascular calcification (VC) is common senescence related degenerative pathology phenomenon in the end-stage of multiple chronic diseases. Mitochondrial dysfunction was often observed in calcified vessels, but the function and mechanism of PolG in the calcification process was still unknown. The present study found PolG D257A/D257A mice presented more severe calcification of aortas than wild type (WT) mice with vitamin D3 (Vit D3) treatment, and this phenomenon was also confirmed in vitro. Mechanistically, PolG could enhance the recruitment and interaction of p53 in calcification condition to recover mitochondrial function and eventually to resist calcification. Meanwhile, we found the mutant PolG (D257A) failed to achieve the same rescue effects, suggesting the 3'-5' exonuclease activity guarantee the enhanced interaction of p53 and PolG in response to calcification stimulation. Thus, we believed that it was PolG, not mutant PolG, could maintain mitochondrial function and attenuate calcification in vitro and in vivo. And PolG could be a novel potential therapeutic target against calcification, providing a novel insight to clinical treatment.

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“…Reducing Insulin growth factor 1 (IGF1)-mediated signaling is directly related to aging and CVD [7]. Importantly, in the heart IGF1 signaling regulates various cellular mechanisms, including growth, metabolic homeostasis [8], and autophagy [9]. For instance, IGF1 ligand and its receptor, IGF1R interaction starts downstream signaling cascades in cardiomyocytes that eventually regulate their differentiation, proliferation, metabolism, hypertrophy [10], and protection from cell death.…”

Section: Introductionmentioning

confidence: 99%

Rewiring of IGF1 secretion and enhanced IGF1R signaling induced by co-chaperone carboxyl-terminus of Hsp70 interacting protein in adipose-derived stem cells provide augmented cardioprotection in aging-hypertensive rats

Barik,

Kuo,

Kuo

et al. 2023

Aging

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Aging-associated cardiovascular diseases depend on the longitudinal deterioration of stem cell dynamics. The entire mechanism behind it is not completely understood. However, many studies suggest that endocrine pathways, particularly the insulin-like growth factor-1(IGF1) signaling pathway are involved in cardioprotection, especially in stem-cell treatments. Here, we investigated the role of a co-chaperone, carboxyl-terminus of Hsp70 interacting protein (CHIP) in the aspects of growth factor secretion and receptor stabilization in mesenchymal stem cells (MSCs). Briefly, we overexpressed CHIP in rat adipose-derived stem cells (rADSCs) and explored the consequences in vitro, and in vivo, in spontaneously hypertensive rats (SHR). Our data revealed that CHIP overexpression in rADSCs promoted the secretion of insulin-like growth factor-1 (IGF1) and IGF binding protein-3 (IGFBP3) as per immunoblot/cytokine array analysis. We also found that these results were dependent on the nuclear translocation of signal transducer and activator of transcription 3 (STAT3) in rADSCs. Further, the CHIP co-chaperone was also involved in the stabilization of the receptor of IGF1 (IGF1R);

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Age‐induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 6 publications

References 73 publications

The role of mtDNA in oocyte quality and embryo development

The role of mtDNA in oocyte quality and embryo development

DNA Polymerase Gamma Recovers Mitochondrial Function and Inhibits Vascular Calcification by Interacted with p53

Rewiring of IGF1 secretion and enhanced IGF1R signaling induced by co-chaperone carboxyl-terminus of Hsp70 interacting protein in adipose-derived stem cells provide augmented cardioprotection in aging-hypertensive rats

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