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

Ramon Cueto; Lixiao Zhang; Hui Min Shan; Xiao Huang; Xinyuan Li; Ya-Feng Li; Jahaira Lopez; William Y Yang; Muriel Lavallee; Catherine Yu; Yong Ji; Xiaofeng Yang; Hong Wang

doi:10.1016/j.redox.2018.03.015

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

Ramon Cueto, Lixiao Zhang, Hui Min Shan, Xiao Huang, Xinyuan Li, Ya-Feng Li, Jahaira Lopez, William Y Yang, Muriel Lavallee, Catherine Yu, Yong Ji, Xiaofeng Yang, Hong Wang

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) which has been implicated in matochondrial (Mt) function impairment. In this study, we characterized Hcy metabolism in mouse tissues by using LC-ESI-MS/MS analysis, established tissue expression profiles for 84 nuclear-encoded Mt electron transport chain complex (nMt-ETC-Com) genes in 20 human and 19 mouse tissues by database mining, and modeled the effect of HHcy on Mt-ETC function. Hcy levels were high in mouse kidney/lung/spleen/liver (24-14 nmol/g tissue) but low in brain/heart (~5 nmol/g). S-adenosylhomocysteine (SAH) levels were high in the liver/kidney (59-33 nmol/g), moderate in lung/heart/brain (7-4 nmol/g) and low in spleen (1 nmol/g). S-adenosylmethionine (SAM) was comparable in all tissues (42-18 nmol/g). SAM/SAH ratio was as high as 25.6 in the spleen but much lower in the heart/lung/brain/kidney/liver (7-0.6). The nMt-ETC-Com genes were highly expressed in muscle/pituitary gland/heart/BM in humans and in lymph node/heart/pancreas/brain in mice. We identified 15 Hcy-suppressive nMt-ETC-Com genes whose mRNA levels were negatively correlated with tissue Hcy levels, including 11 complex-I, one complex-IV and two complex-V genes. Among the 11 Hcy-suppressive complex-I genes, 4 are complex-I core subunits. Based on the pattern of tissue expression of these genes, we classified tissues into three tiers (high/mid/low-Hcy responsive), and defined heart/eye/pancreas/brain/kidney/liver/testis/embryonic tissues as tier 1 (high-Hcy responsive) tissues in both human and mice. Furthermore, through extensive literature mining, we found that most of the Hcy-suppressive nMt-ETC-Com genes were suppressed in HHcy conditions and related with Mt complex assembly/activity impairment in human disease and experimental models. We hypothesize that HHcy inhibits Mt complex I gene expression leading to Mt dysfunction.

Original language	American English
Pages (from-to)	70-88
Number of pages	19
Journal	Redox Biology
Volume	17
DOIs	https://doi.org/10.1016/j.redox.2018.03.015
State	Published - Jun 2018
Externally published	Yes

Keywords

Animals
Cardiovascular Diseases/genetics
Electron Transport Chain Complex Proteins/genetics
Gene Expression Regulation/genetics
Humans
Hyperhomocysteinemia/genetics
Kidney/metabolism
Lung/metabolism
Mice
Mitochondria/genetics
Organ Specificity
Risk Factors
S-Adenosylmethionine/metabolism
Spleen/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.redox.2018.03.015

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@article{4632e2ebec304aad9f027bae1228d7c0,

title = "Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile - Novel hypothesis establishment",

abstract = "Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) which has been implicated in matochondrial (Mt) function impairment. In this study, we characterized Hcy metabolism in mouse tissues by using LC-ESI-MS/MS analysis, established tissue expression profiles for 84 nuclear-encoded Mt electron transport chain complex (nMt-ETC-Com) genes in 20 human and 19 mouse tissues by database mining, and modeled the effect of HHcy on Mt-ETC function. Hcy levels were high in mouse kidney/lung/spleen/liver (24-14 nmol/g tissue) but low in brain/heart (\textasciitilde{}5 nmol/g). S-adenosylhomocysteine (SAH) levels were high in the liver/kidney (59-33 nmol/g), moderate in lung/heart/brain (7-4 nmol/g) and low in spleen (1 nmol/g). S-adenosylmethionine (SAM) was comparable in all tissues (42-18 nmol/g). SAM/SAH ratio was as high as 25.6 in the spleen but much lower in the heart/lung/brain/kidney/liver (7-0.6). The nMt-ETC-Com genes were highly expressed in muscle/pituitary gland/heart/BM in humans and in lymph node/heart/pancreas/brain in mice. We identified 15 Hcy-suppressive nMt-ETC-Com genes whose mRNA levels were negatively correlated with tissue Hcy levels, including 11 complex-I, one complex-IV and two complex-V genes. Among the 11 Hcy-suppressive complex-I genes, 4 are complex-I core subunits. Based on the pattern of tissue expression of these genes, we classified tissues into three tiers (high/mid/low-Hcy responsive), and defined heart/eye/pancreas/brain/kidney/liver/testis/embryonic tissues as tier 1 (high-Hcy responsive) tissues in both human and mice. Furthermore, through extensive literature mining, we found that most of the Hcy-suppressive nMt-ETC-Com genes were suppressed in HHcy conditions and related with Mt complex assembly/activity impairment in human disease and experimental models. We hypothesize that HHcy inhibits Mt complex I gene expression leading to Mt dysfunction.",

keywords = "Animals, Cardiovascular Diseases/genetics, Electron Transport Chain Complex Proteins/genetics, Gene Expression Regulation/genetics, Humans, Hyperhomocysteinemia/genetics, Kidney/metabolism, Lung/metabolism, Mice, Mitochondria/genetics, Organ Specificity, Risk Factors, S-Adenosylmethionine/metabolism, Spleen/metabolism",

author = "Ramon Cueto and Lixiao Zhang and Shan, \{Hui Min\} and Xiao Huang and Xinyuan Li and Ya-Feng Li and Jahaira Lopez and Yang, \{William Y\} and Muriel Lavallee and Catherine Yu and Yong Ji and Xiaofeng Yang and Hong Wang",

year = "2018",

month = jun,

doi = "10.1016/j.redox.2018.03.015",

language = "American English",

volume = "17",

pages = "70--88",

journal = "Redox Biology",

issn = "2213-2317",

publisher = "Elsevier B.V.",

}

TY - JOUR

T1 - Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile - Novel hypothesis establishment

AU - Cueto, Ramon

AU - Zhang, Lixiao

AU - Shan, Hui Min

AU - Huang, Xiao

AU - Li, Xinyuan

AU - Li, Ya-Feng

AU - Lopez, Jahaira

AU - Yang, William Y

AU - Lavallee, Muriel

AU - Yu, Catherine

AU - Ji, Yong

AU - Yang, Xiaofeng

AU - Wang, Hong

PY - 2018/6

Y1 - 2018/6

N2 - Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) which has been implicated in matochondrial (Mt) function impairment. In this study, we characterized Hcy metabolism in mouse tissues by using LC-ESI-MS/MS analysis, established tissue expression profiles for 84 nuclear-encoded Mt electron transport chain complex (nMt-ETC-Com) genes in 20 human and 19 mouse tissues by database mining, and modeled the effect of HHcy on Mt-ETC function. Hcy levels were high in mouse kidney/lung/spleen/liver (24-14 nmol/g tissue) but low in brain/heart (~5 nmol/g). S-adenosylhomocysteine (SAH) levels were high in the liver/kidney (59-33 nmol/g), moderate in lung/heart/brain (7-4 nmol/g) and low in spleen (1 nmol/g). S-adenosylmethionine (SAM) was comparable in all tissues (42-18 nmol/g). SAM/SAH ratio was as high as 25.6 in the spleen but much lower in the heart/lung/brain/kidney/liver (7-0.6). The nMt-ETC-Com genes were highly expressed in muscle/pituitary gland/heart/BM in humans and in lymph node/heart/pancreas/brain in mice. We identified 15 Hcy-suppressive nMt-ETC-Com genes whose mRNA levels were negatively correlated with tissue Hcy levels, including 11 complex-I, one complex-IV and two complex-V genes. Among the 11 Hcy-suppressive complex-I genes, 4 are complex-I core subunits. Based on the pattern of tissue expression of these genes, we classified tissues into three tiers (high/mid/low-Hcy responsive), and defined heart/eye/pancreas/brain/kidney/liver/testis/embryonic tissues as tier 1 (high-Hcy responsive) tissues in both human and mice. Furthermore, through extensive literature mining, we found that most of the Hcy-suppressive nMt-ETC-Com genes were suppressed in HHcy conditions and related with Mt complex assembly/activity impairment in human disease and experimental models. We hypothesize that HHcy inhibits Mt complex I gene expression leading to Mt dysfunction.

AB - Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) which has been implicated in matochondrial (Mt) function impairment. In this study, we characterized Hcy metabolism in mouse tissues by using LC-ESI-MS/MS analysis, established tissue expression profiles for 84 nuclear-encoded Mt electron transport chain complex (nMt-ETC-Com) genes in 20 human and 19 mouse tissues by database mining, and modeled the effect of HHcy on Mt-ETC function. Hcy levels were high in mouse kidney/lung/spleen/liver (24-14 nmol/g tissue) but low in brain/heart (~5 nmol/g). S-adenosylhomocysteine (SAH) levels were high in the liver/kidney (59-33 nmol/g), moderate in lung/heart/brain (7-4 nmol/g) and low in spleen (1 nmol/g). S-adenosylmethionine (SAM) was comparable in all tissues (42-18 nmol/g). SAM/SAH ratio was as high as 25.6 in the spleen but much lower in the heart/lung/brain/kidney/liver (7-0.6). The nMt-ETC-Com genes were highly expressed in muscle/pituitary gland/heart/BM in humans and in lymph node/heart/pancreas/brain in mice. We identified 15 Hcy-suppressive nMt-ETC-Com genes whose mRNA levels were negatively correlated with tissue Hcy levels, including 11 complex-I, one complex-IV and two complex-V genes. Among the 11 Hcy-suppressive complex-I genes, 4 are complex-I core subunits. Based on the pattern of tissue expression of these genes, we classified tissues into three tiers (high/mid/low-Hcy responsive), and defined heart/eye/pancreas/brain/kidney/liver/testis/embryonic tissues as tier 1 (high-Hcy responsive) tissues in both human and mice. Furthermore, through extensive literature mining, we found that most of the Hcy-suppressive nMt-ETC-Com genes were suppressed in HHcy conditions and related with Mt complex assembly/activity impairment in human disease and experimental models. We hypothesize that HHcy inhibits Mt complex I gene expression leading to Mt dysfunction.

KW - Animals

KW - Cardiovascular Diseases/genetics

KW - Electron Transport Chain Complex Proteins/genetics

KW - Gene Expression Regulation/genetics

KW - Humans

KW - Hyperhomocysteinemia/genetics

KW - Kidney/metabolism

KW - Lung/metabolism

KW - Mice

KW - Mitochondria/genetics

KW - Organ Specificity

KW - Risk Factors

KW - S-Adenosylmethionine/metabolism

KW - Spleen/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85045620636&partnerID=8YFLogxK

U2 - 10.1016/j.redox.2018.03.015

DO - 10.1016/j.redox.2018.03.015

M3 - Article

C2 - 29679893

SN - 2213-2317

VL - 17

SP - 70

EP - 88

JO - Redox Biology

JF - Redox Biology

ER -

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

Abstract

Keywords

UN SDGs

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