Aging-Related Increase of cGMP Disrupts Mitochondrial Homeostasis in Leydig Cells
Abstract Since mitochondria play an essential role in the testosterone biosynthesis, serve as power centers and are a source of oxidative stress, a possible mitochondrial dysfunction could be connected with decreased activity of Leydig cells and lowered testosterone production during aging. Here we...
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| Veröffentlicht in: | The journals of gerontology. Series A, Biological sciences and medical sciences Biological sciences and medical sciences, 2021-02, Vol.76 (2), p.177-186 |
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| container_title | The journals of gerontology. Series A, Biological sciences and medical sciences |
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| creator | Sokanovic, Srdjan J Baburski, Aleksandar Z Kojic, Zvezdana Medar, Marija L J Andric, Silvana A Kostic, Tatjana S |
| description | Abstract
Since mitochondria play an essential role in the testosterone biosynthesis, serve as power centers and are a source of oxidative stress, a possible mitochondrial dysfunction could be connected with decreased activity of Leydig cells and lowered testosterone production during aging. Here we chronologically analyzed age-related alterations of mitochondrial function in Leydig cells correlated by the progressive rise of cGMP signaling and with respect to testosterone synthesis. To target cGMP signaling in Leydig cells, acute or long-term in vivo or ex vivo treatments with sildenafil (phosphodiesterase 5 [PDE5] inhibitor) were performed. Aging-related accumulation of cGMP in the Leydig cells is associated with mitochondrial dysfunction illustrated by reduced ATP and steroid production, lowered O2 consumption, increased mitochondrial abundance and mtDNA copies number, decreased expression of genes that regulate mitochondrial biogenesis (Ppargc1a/PGC1a-Tfam-Nrf1/NRF1), mitophagy (Pink1), fusion (Mfn1, Opa1), and increased Nrf2/NRF2. Acute in vivo PDE5 inhibition overaccumulated cGMP and stimulated testosterone but reduced ATP production in Leydig cells from adult, middle-aged, and old rats. The increased ATP/O ratio observed in cells from old compared to adult rats was diminished after stimulation of cGMP signaling. Opposite, long-term PDE5 inhibition decreased cGMP signaling and improved mitochondrial function/dynamics in Leydig cells from old rats. Mitochondrial abundance in Leydig cells decreased while ATP levels increased. Chronic treatment elevated Tfam, Nrf1, Nrf2, Opa1, Mfn1, Drp1, and normalized Pink1 expression. Altogether, long-term PDE5 inhibition prevented age-related NO and cGMP elevation, improved mitochondrial dynamics/function, and testosterone production. The results pointed on cGMP signaling in Leydig cells as a target for pharmacological manipulation of aging-associated changes in mitochondrial function and testosterone production. |
| doi_str_mv | 10.1093/gerona/glaa132 |
| format | Article |
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Since mitochondria play an essential role in the testosterone biosynthesis, serve as power centers and are a source of oxidative stress, a possible mitochondrial dysfunction could be connected with decreased activity of Leydig cells and lowered testosterone production during aging. Here we chronologically analyzed age-related alterations of mitochondrial function in Leydig cells correlated by the progressive rise of cGMP signaling and with respect to testosterone synthesis. To target cGMP signaling in Leydig cells, acute or long-term in vivo or ex vivo treatments with sildenafil (phosphodiesterase 5 [PDE5] inhibitor) were performed. Aging-related accumulation of cGMP in the Leydig cells is associated with mitochondrial dysfunction illustrated by reduced ATP and steroid production, lowered O2 consumption, increased mitochondrial abundance and mtDNA copies number, decreased expression of genes that regulate mitochondrial biogenesis (Ppargc1a/PGC1a-Tfam-Nrf1/NRF1), mitophagy (Pink1), fusion (Mfn1, Opa1), and increased Nrf2/NRF2. Acute in vivo PDE5 inhibition overaccumulated cGMP and stimulated testosterone but reduced ATP production in Leydig cells from adult, middle-aged, and old rats. The increased ATP/O ratio observed in cells from old compared to adult rats was diminished after stimulation of cGMP signaling. Opposite, long-term PDE5 inhibition decreased cGMP signaling and improved mitochondrial function/dynamics in Leydig cells from old rats. Mitochondrial abundance in Leydig cells decreased while ATP levels increased. Chronic treatment elevated Tfam, Nrf1, Nrf2, Opa1, Mfn1, Drp1, and normalized Pink1 expression. Altogether, long-term PDE5 inhibition prevented age-related NO and cGMP elevation, improved mitochondrial dynamics/function, and testosterone production. The results pointed on cGMP signaling in Leydig cells as a target for pharmacological manipulation of aging-associated changes in mitochondrial function and testosterone production.</description><identifier>ISSN: 1079-5006</identifier><identifier>EISSN: 1758-535X</identifier><identifier>DOI: 10.1093/gerona/glaa132</identifier><identifier>PMID: 32459846</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Aging ; Biosynthesis ; Cells ; Cyclic GMP ; Homeostasis ; Leydig cells ; Mitochondria ; Mitochondrial DNA ; Oxidative stress ; Oxygen consumption ; Phosphodiesterase ; PTEN-induced putative kinase ; Sildenafil ; Testosterone</subject><ispartof>The journals of gerontology. Series A, Biological sciences and medical sciences, 2021-02, Vol.76 (2), p.177-186</ispartof><rights>The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. 2020</rights><rights>The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</rights><rights>Copyright Oxford University Press Feb 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c357t-cbf39044884eb960e51090051c392be37716e05df6071088723233d17760443a3</citedby><cites>FETCH-LOGICAL-c357t-cbf39044884eb960e51090051c392be37716e05df6071088723233d17760443a3</cites><orcidid>0000-0003-3440-8998</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1583,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32459846$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Le Couteur, David</contributor><creatorcontrib>Sokanovic, Srdjan J</creatorcontrib><creatorcontrib>Baburski, Aleksandar Z</creatorcontrib><creatorcontrib>Kojic, Zvezdana</creatorcontrib><creatorcontrib>Medar, Marija L J</creatorcontrib><creatorcontrib>Andric, Silvana A</creatorcontrib><creatorcontrib>Kostic, Tatjana S</creatorcontrib><title>Aging-Related Increase of cGMP Disrupts Mitochondrial Homeostasis in Leydig Cells</title><title>The journals of gerontology. Series A, Biological sciences and medical sciences</title><addtitle>J Gerontol A Biol Sci Med Sci</addtitle><description>Abstract
Since mitochondria play an essential role in the testosterone biosynthesis, serve as power centers and are a source of oxidative stress, a possible mitochondrial dysfunction could be connected with decreased activity of Leydig cells and lowered testosterone production during aging. Here we chronologically analyzed age-related alterations of mitochondrial function in Leydig cells correlated by the progressive rise of cGMP signaling and with respect to testosterone synthesis. To target cGMP signaling in Leydig cells, acute or long-term in vivo or ex vivo treatments with sildenafil (phosphodiesterase 5 [PDE5] inhibitor) were performed. Aging-related accumulation of cGMP in the Leydig cells is associated with mitochondrial dysfunction illustrated by reduced ATP and steroid production, lowered O2 consumption, increased mitochondrial abundance and mtDNA copies number, decreased expression of genes that regulate mitochondrial biogenesis (Ppargc1a/PGC1a-Tfam-Nrf1/NRF1), mitophagy (Pink1), fusion (Mfn1, Opa1), and increased Nrf2/NRF2. Acute in vivo PDE5 inhibition overaccumulated cGMP and stimulated testosterone but reduced ATP production in Leydig cells from adult, middle-aged, and old rats. The increased ATP/O ratio observed in cells from old compared to adult rats was diminished after stimulation of cGMP signaling. Opposite, long-term PDE5 inhibition decreased cGMP signaling and improved mitochondrial function/dynamics in Leydig cells from old rats. Mitochondrial abundance in Leydig cells decreased while ATP levels increased. Chronic treatment elevated Tfam, Nrf1, Nrf2, Opa1, Mfn1, Drp1, and normalized Pink1 expression. Altogether, long-term PDE5 inhibition prevented age-related NO and cGMP elevation, improved mitochondrial dynamics/function, and testosterone production. The results pointed on cGMP signaling in Leydig cells as a target for pharmacological manipulation of aging-associated changes in mitochondrial function and testosterone production.</description><subject>Aging</subject><subject>Biosynthesis</subject><subject>Cells</subject><subject>Cyclic GMP</subject><subject>Homeostasis</subject><subject>Leydig cells</subject><subject>Mitochondria</subject><subject>Mitochondrial DNA</subject><subject>Oxidative stress</subject><subject>Oxygen consumption</subject><subject>Phosphodiesterase</subject><subject>PTEN-induced putative kinase</subject><subject>Sildenafil</subject><subject>Testosterone</subject><issn>1079-5006</issn><issn>1758-535X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNqFkDtPwzAURi0EolBYGZElFhjS-hHHyVgVaCu14iGQ2CI3uQmukjjYydB_j6sWBhbu4juc--nzQeiKkhElCR-XYE2jxmWlFOXsCJ1RKeJAcPFx7Hcik0AQEg3QuXMbshvBTtGAs1AkcRidoZdJqZsyeIVKdZDjRZNZUA6wKXA2Wz3je-1s33YOr3Rnsk_T5FarCs9NDcZ1ymmHdYOXsM11iadQVe4CnRSqcnB5eIfo_fHhbToPlk-zxXSyDDIuZBdk64InJAzjOIR1EhEQ_j--Hs14wtbApaQREJEXEZGUxLFknHGeUykjf8UVH6LbfW5rzVcPrktr7TLfQDVgepeykHgVjEWhR2_-oBvT28a381TMo5CRRHpqtKcya5yzUKSt1bWy25SSdCc73ctOD7L9wfUhtl_XkP_iP3Y9cLcHTN_-F_YNCZSH8A</recordid><startdate>20210201</startdate><enddate>20210201</enddate><creator>Sokanovic, Srdjan J</creator><creator>Baburski, Aleksandar Z</creator><creator>Kojic, Zvezdana</creator><creator>Medar, Marija L J</creator><creator>Andric, Silvana A</creator><creator>Kostic, Tatjana S</creator><general>Oxford University Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3440-8998</orcidid></search><sort><creationdate>20210201</creationdate><title>Aging-Related Increase of cGMP Disrupts Mitochondrial Homeostasis in Leydig Cells</title><author>Sokanovic, Srdjan J ; Baburski, Aleksandar Z ; Kojic, Zvezdana ; Medar, Marija L J ; Andric, Silvana A ; Kostic, Tatjana S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c357t-cbf39044884eb960e51090051c392be37716e05df6071088723233d17760443a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Aging</topic><topic>Biosynthesis</topic><topic>Cells</topic><topic>Cyclic GMP</topic><topic>Homeostasis</topic><topic>Leydig cells</topic><topic>Mitochondria</topic><topic>Mitochondrial DNA</topic><topic>Oxidative stress</topic><topic>Oxygen consumption</topic><topic>Phosphodiesterase</topic><topic>PTEN-induced putative kinase</topic><topic>Sildenafil</topic><topic>Testosterone</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sokanovic, Srdjan J</creatorcontrib><creatorcontrib>Baburski, Aleksandar Z</creatorcontrib><creatorcontrib>Kojic, Zvezdana</creatorcontrib><creatorcontrib>Medar, Marija L J</creatorcontrib><creatorcontrib>Andric, Silvana A</creatorcontrib><creatorcontrib>Kostic, Tatjana S</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>The journals of gerontology. Series A, Biological sciences and medical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sokanovic, Srdjan J</au><au>Baburski, Aleksandar Z</au><au>Kojic, Zvezdana</au><au>Medar, Marija L J</au><au>Andric, Silvana A</au><au>Kostic, Tatjana S</au><au>Le Couteur, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aging-Related Increase of cGMP Disrupts Mitochondrial Homeostasis in Leydig Cells</atitle><jtitle>The journals of gerontology. Series A, Biological sciences and medical sciences</jtitle><addtitle>J Gerontol A Biol Sci Med Sci</addtitle><date>2021-02-01</date><risdate>2021</risdate><volume>76</volume><issue>2</issue><spage>177</spage><epage>186</epage><pages>177-186</pages><issn>1079-5006</issn><eissn>1758-535X</eissn><abstract>Abstract
Since mitochondria play an essential role in the testosterone biosynthesis, serve as power centers and are a source of oxidative stress, a possible mitochondrial dysfunction could be connected with decreased activity of Leydig cells and lowered testosterone production during aging. Here we chronologically analyzed age-related alterations of mitochondrial function in Leydig cells correlated by the progressive rise of cGMP signaling and with respect to testosterone synthesis. To target cGMP signaling in Leydig cells, acute or long-term in vivo or ex vivo treatments with sildenafil (phosphodiesterase 5 [PDE5] inhibitor) were performed. Aging-related accumulation of cGMP in the Leydig cells is associated with mitochondrial dysfunction illustrated by reduced ATP and steroid production, lowered O2 consumption, increased mitochondrial abundance and mtDNA copies number, decreased expression of genes that regulate mitochondrial biogenesis (Ppargc1a/PGC1a-Tfam-Nrf1/NRF1), mitophagy (Pink1), fusion (Mfn1, Opa1), and increased Nrf2/NRF2. Acute in vivo PDE5 inhibition overaccumulated cGMP and stimulated testosterone but reduced ATP production in Leydig cells from adult, middle-aged, and old rats. The increased ATP/O ratio observed in cells from old compared to adult rats was diminished after stimulation of cGMP signaling. Opposite, long-term PDE5 inhibition decreased cGMP signaling and improved mitochondrial function/dynamics in Leydig cells from old rats. Mitochondrial abundance in Leydig cells decreased while ATP levels increased. Chronic treatment elevated Tfam, Nrf1, Nrf2, Opa1, Mfn1, Drp1, and normalized Pink1 expression. Altogether, long-term PDE5 inhibition prevented age-related NO and cGMP elevation, improved mitochondrial dynamics/function, and testosterone production. The results pointed on cGMP signaling in Leydig cells as a target for pharmacological manipulation of aging-associated changes in mitochondrial function and testosterone production.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>32459846</pmid><doi>10.1093/gerona/glaa132</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-3440-8998</orcidid></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Aging Biosynthesis Cells Cyclic GMP Homeostasis Leydig cells Mitochondria Mitochondrial DNA Oxidative stress Oxygen consumption Phosphodiesterase PTEN-induced putative kinase Sildenafil Testosterone |
| title | Aging-Related Increase of cGMP Disrupts Mitochondrial Homeostasis in Leydig Cells |
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