Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile – Novel hypothesis establishment

Cueto, Ramón; Zhang, Lixiao; Shan, Hui; Huang, Xiao; Li, Xinyuan; Li, Yafeng; Lopez, Jahaira; Yang, William Y.; Lavallee, Muriel; Yu, Catherine; Ji, Yong; Yang, Xiaofeng; Wang, Hong

doi:10.1016/j.redox.2018.03.015

Cited by 27 publications

(29 citation statements)

References 85 publications

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“…29,30 p27 can block the cell cycle in G0/G1 phase by negatively regulation of cyclin/CDK complexes, and PCNA is a well-known molecular marker for cell proliferation because of the role of replication in S phase, which could coordinate with p27 in the regulation of cell cycle. 31,32 In this study, we found 100 μmol/L Hcy was also used in other studies 33,34 to explore the effects of Hcy on VSMCs proliferation and human aortic smooth muscle cells (HASMC) mitochondrial dysfunction and it was showed The pathogenesis of atherosclerosis involves changes in the expression and function of a series of genes, and VSMCs proliferation is precisely regulated by various proliferation related genes, particularly the mitogenic genes. MFN2 is a newly discovered cell proliferation inhibitor that localize in the mitochondrial outer membrane and it plays an essential role in mitochondrial fusion, mitochondrial morphology in mammalian cells, yeasts, and flies.…”

Section: Discussionmentioning

confidence: 99%

Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis

Hao

et al. 2019

J Cellular Molecular Medi

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It is well‐established that homocysteine (Hcy) is an independent risk factor for atherosclerosis. Hcy can promote vascular smooth muscle cell (VSMC) proliferation, it plays a key role in neointimal formation and thus contribute to arteriosclerosis. However, the molecular mechanism on VSMCs proliferation underlying atherosclerosis is not well elucidated. Mitofusin‐2 (MFN2) is an important transmembrane GTPase in the mitochondrial outer membrane and it can block cells in the G0/G1 stage of the cell cycle. To investigate the contribution of aberrant MFN2 transcription in Hcy‐induced VSMCs proliferation and the underlying mechanisms. Cell cycle analysis revealed a decreased proportion of VSMCs in G0/G1 and an increased proportion in S phase in atherosclerotic plaque of APOE −/− mice with hyperhomocystinaemia (HHcy) as well as in VSMCs exposed to Hcy in vitro. The DNA methylation level of MFN2 promoter was obviously increased in VSMCs treated with Hcy, leading to suppressed promoter activity and low expression of MFN2. In addition, we found that the expression of c‐Myc was increased in atherosclerotic plaque and VSMCs treated with Hcy. Further study showed that c‐Myc indirectly regulates MFN2 expression is duo to the binding of c‐Myc to DNMT1 promoter up‐regulates DNMT1 expression leading to DNA hypermethylation of MFN2 promoter, thereby inhibits MFN2 expression in VSMCs treated with Hcy. In conclusion, our study demonstrated that Hcy‐induced hypermethylation of MFN2 promoter inhibits the transcription of MFN2, leading to VSMCs proliferation in plaque formation, and the increased binding of c‐Myc to DNMT1 promoter is a new and relevant molecular mechanism.

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Section: Discussionmentioning

confidence: 99%

Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis

Hao

et al. 2019

J Cellular Molecular Medi

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“…The purpose of the current study is to evaluate extended HM cycle gene expression in disease conditions, which is a different strategy compared with our previous database mining studies. In our previous studies, we examined tissue expression profile of 12 core HM cycle genes and 97 genes in the mitochondrial electron transport chain (ETC) complexes in 20 normal human and 19 normal mouse tissues [54,57]. We established the correlation of gene expression with HM cycle metabolites, including Hcy, SAM, SAH and SAM/SAH ratio in mice [54,57] and examined differential gene expression among different cell types and tissues [58].…”

Section: Discussionmentioning

confidence: 99%

“…1A) [53]. These datasets were analyzed utilizing GEO2R from GEO databases as we previously described [52,54]. Differentially expressed genes were defined as p -value ≤ 0.05 and absolute fold change ≥2.…”

Section: Methodsmentioning

confidence: 99%

Homocysteine-methionine cycle is a metabolic sensor system controlling methylation-regulated pathological signaling

et al. 2020

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Homocysteine-Methionine (HM) cycle produces universal methyl group donor S-adenosylmethione (SAM), methyltransferase inhibitor S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hyperhomocysteinemia (HHcy) is established as an independent risk factor for cardiovascular disease (CVD) and other degenerative disease.We selected 115 genes in the extended HM cycle (31 metabolic enzymes and 84 methyltransferases), examined their protein subcellular location/partner protein, investigated their mRNA levels and mapped their corresponding histone methylation status in 35 disease conditions via mining a set of public databases and intensive literature research. We have 6 major findings. 1) All HM metabolic enzymes are located only in the cytosol except for cystathionine-β-synthase (CBS), which was identified in both cytosol and nucleus. 2) Eight disease conditions encountered only histone hypomethylation on 8 histone residues (H3R2/K4/R8/K9/K27/K36/K79 and H4R3). Nine disease conditions had only histone hypermethylation on 8 histone residues (H3R2/K4/K9/K27/K36/K79 and H4R3/K20). 3) We classified 9 disease types with differential HM cycle expression pattern. Eleven disease conditions presented most 4 HM cycle pathway suppression. 4) Three disease conditions had all 4 HM cycle pathway suppression and only histone hypomethylation on H3R2/K4/R8/K9/K36 and H4R3. 5) Eleven HM cycle metabolic enzymes interact with 955 proteins. 6) Five paired HM cycle proteins interact with each other.We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent metabolism-associated danger signal recognition and modulates SAM/SAH-dependent methylation in disease conditions and that hypomethylation on frequently modified histone residues is a key mechanism for metabolic disorders, autoimmune disease and CVD. We propose that HM metabolism takes place in the cytosol, that nuclear methylation equilibration requires a nuclear-cytosol transfer of SAM/SAH/Hcy, and that Hcy clearance is essential for genetic protection.

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“…Hcy-mediated hypomethylation of DNA and histone modifications impair epigenetic control of gene expression and may contribute to pathogenesis of various HHcy-related human diseases [ 18 ]. Recent comprehensive data mining analyses in human and mouse tissues revealed that 15 nuclear-encoded genes for ETC complex proteins are suppressed in HHcy [ 94 ]. Among the identified genes, eleven were of ETC complex I, one of complex IV and two of complex V. Since 4 of the 11 Hcy-suppressed genes of complex I encode core subunits, which are indispensable for activity, the authors suggest that dysfunction of complex I due to alterations in gene expression may play a primary role in Hcy-induced pathogenicity.…”

Section: Homocysteine and Mitochondrial Oxidative Stressmentioning

confidence: 99%

Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems

Kaplán

Tatarková

Sivoňová

et al. 2020

IJMS

125

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Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and neurodegenerative diseases. Accumulating evidence indicates that pathophysiology of these diseases is linked with mitochondrial dysfunction. In this review, we discuss the current knowledge concerning the effects of HHcy on mitochondrial homeostasis, including energy metabolism, mitochondrial apoptotic pathway, and mitochondrial dynamics. The recent studies suggest that the interaction between Hcy and mitochondria is complex, and reactive oxygen species (ROS) are possible mediators of Hcy effects. We focus on mechanisms contributing to HHcy-associated oxidative stress, such as sources of ROS generation and alterations in antioxidant defense resulting from altered gene expression and post-translational modifications of proteins. Moreover, we discuss some recent findings suggesting that HHcy may have beneficial effects on mitochondrial ROS homeostasis and antioxidant defense. A better understanding of complex mechanisms through which Hcy affects mitochondrial functions could contribute to the development of more specific therapeutic strategies targeted at HHcy-associated disorders.

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Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile – Novel hypothesis establishment

Cited by 27 publications

References 85 publications

Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis

Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis

Homocysteine-methionine cycle is a metabolic sensor system controlling methylation-regulated pathological signaling

Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems

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