Regulation of AMPK activity by type 10 adenylyl cyclase: contribution to the mitochondrial biology, cellular redox and energy homeostasis
The downregulation of AMP-activated protein kinase (AMPK) activity contributes to numerous pathologies. Recent reports suggest that the elevation of cellular cAMP promotes AMPK activity. However, the source of the cAMP pool that controls AMPK activity remains unknown. Mammalian cells possess two cAM...
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| Veröffentlicht in: | Cellular and molecular life sciences : CMLS 2019-12, Vol.76 (24), p.4945-4959 |
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| creator | Jayarajan, Vignesh Appukuttan, Avinash Aslam, Muhammad Reusch, Peter Regitz-Zagrosek, Vera Ladilov, Yury |
| description | The downregulation of AMP-activated protein kinase (AMPK) activity contributes to numerous pathologies. Recent reports suggest that the elevation of cellular cAMP promotes AMPK activity. However, the source of the cAMP pool that controls AMPK activity remains unknown. Mammalian cells possess two cAMP sources: membrane-bound adenylyl cyclase (tmAC) and intracellularly localized, type 10 soluble adenylyl cyclase (sAC). Due to the localization of sAC and AMPK in similar intracellular compartments, we hypothesized that sAC may control AMPK activity. In this study, sAC expression and activity were manipulated in H9C2 cells, adult rat cardiomyocytes or endothelial cells. sAC knockdown depleted the cellular cAMP content and decreased AMPK activity in an EPAC-dependent manner. Functionally, sAC knockdown reduced cellular ATP content, increased mitochondrial ROS formation and led to mitochondrial depolarization. Furthermore, sAC downregulation led to EPAC-dependent mitophagy disturbance, indicated by an increased mitochondrial mass and unaffected mitochondrial biogenesis. Consistently, sAC overexpression or stimulation with bicarbonate significantly increased AMPK activity and cellular ATP content. In contrast, tmAC inhibition or stimulation produced no effect on AMPK activity. Therefore, the sAC–EPAC axis may regulate basal and induced AMPK activity and support mitophagy, cellular energy and redox homeostasis. The study argues for sAC as a potential target in treating pathologies associated with AMPK downregulation. |
| doi_str_mv | 10.1007/s00018-019-03152-y |
| format | Article |
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Recent reports suggest that the elevation of cellular cAMP promotes AMPK activity. However, the source of the cAMP pool that controls AMPK activity remains unknown. Mammalian cells possess two cAMP sources: membrane-bound adenylyl cyclase (tmAC) and intracellularly localized, type 10 soluble adenylyl cyclase (sAC). Due to the localization of sAC and AMPK in similar intracellular compartments, we hypothesized that sAC may control AMPK activity. In this study, sAC expression and activity were manipulated in H9C2 cells, adult rat cardiomyocytes or endothelial cells. sAC knockdown depleted the cellular cAMP content and decreased AMPK activity in an EPAC-dependent manner. Functionally, sAC knockdown reduced cellular ATP content, increased mitochondrial ROS formation and led to mitochondrial depolarization. Furthermore, sAC downregulation led to EPAC-dependent mitophagy disturbance, indicated by an increased mitochondrial mass and unaffected mitochondrial biogenesis. Consistently, sAC overexpression or stimulation with bicarbonate significantly increased AMPK activity and cellular ATP content. In contrast, tmAC inhibition or stimulation produced no effect on AMPK activity. Therefore, the sAC–EPAC axis may regulate basal and induced AMPK activity and support mitophagy, cellular energy and redox homeostasis. The study argues for sAC as a potential target in treating pathologies associated with AMPK downregulation.</description><identifier>ISSN: 1420-682X</identifier><identifier>EISSN: 1420-9071</identifier><identifier>DOI: 10.1007/s00018-019-03152-y</identifier><identifier>PMID: 31172217</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Adenylyl Cyclases - genetics ; Adenylyl Cyclases - metabolism ; AMP-activated protein kinase ; AMP-Activated Protein Kinase Kinases ; Animals ; Bicarbonates ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cardiomyocytes ; Cell Biology ; Cell Physiological Phenomena ; Cyclic AMP ; Cyclic AMP - genetics ; Cyclic AMP - metabolism ; Depolarization ; Endothelial cells ; Endothelial Cells - metabolism ; Energy balance ; Energy Metabolism - genetics ; Guanine Nucleotide Exchange Factors - genetics ; Homeostasis ; Humans ; Kinases ; Life Sciences ; Localization ; Mammalian cells ; Mitochondria ; Mitochondria - genetics ; Mitochondria - metabolism ; Myocytes, Cardiac - metabolism ; Original ; Original Article ; Oxidation-Reduction ; Phosphates ; Phosphorylation ; Protein Kinases - genetics ; Rats ; Stimulation</subject><ispartof>Cellular and molecular life sciences : CMLS, 2019-12, Vol.76 (24), p.4945-4959</ispartof><rights>Springer Nature Switzerland AG 2019</rights><rights>Cellular and Molecular Life Sciences is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-8452270bc6d408f043c3dbc5c33426e32f97e84eb6e2994ba276f8b35b5ee87e3</citedby><cites>FETCH-LOGICAL-c541t-8452270bc6d408f043c3dbc5c33426e32f97e84eb6e2994ba276f8b35b5ee87e3</cites><orcidid>0000-0002-8529-4217 ; 0000-0002-9836-8801</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11105217/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11105217/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31172217$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jayarajan, Vignesh</creatorcontrib><creatorcontrib>Appukuttan, Avinash</creatorcontrib><creatorcontrib>Aslam, Muhammad</creatorcontrib><creatorcontrib>Reusch, Peter</creatorcontrib><creatorcontrib>Regitz-Zagrosek, Vera</creatorcontrib><creatorcontrib>Ladilov, Yury</creatorcontrib><title>Regulation of AMPK activity by type 10 adenylyl cyclase: contribution to the mitochondrial biology, cellular redox and energy homeostasis</title><title>Cellular and molecular life sciences : CMLS</title><addtitle>Cell. Mol. Life Sci</addtitle><addtitle>Cell Mol Life Sci</addtitle><description>The downregulation of AMP-activated protein kinase (AMPK) activity contributes to numerous pathologies. Recent reports suggest that the elevation of cellular cAMP promotes AMPK activity. However, the source of the cAMP pool that controls AMPK activity remains unknown. Mammalian cells possess two cAMP sources: membrane-bound adenylyl cyclase (tmAC) and intracellularly localized, type 10 soluble adenylyl cyclase (sAC). Due to the localization of sAC and AMPK in similar intracellular compartments, we hypothesized that sAC may control AMPK activity. In this study, sAC expression and activity were manipulated in H9C2 cells, adult rat cardiomyocytes or endothelial cells. sAC knockdown depleted the cellular cAMP content and decreased AMPK activity in an EPAC-dependent manner. Functionally, sAC knockdown reduced cellular ATP content, increased mitochondrial ROS formation and led to mitochondrial depolarization. Furthermore, sAC downregulation led to EPAC-dependent mitophagy disturbance, indicated by an increased mitochondrial mass and unaffected mitochondrial biogenesis. Consistently, sAC overexpression or stimulation with bicarbonate significantly increased AMPK activity and cellular ATP content. In contrast, tmAC inhibition or stimulation produced no effect on AMPK activity. Therefore, the sAC–EPAC axis may regulate basal and induced AMPK activity and support mitophagy, cellular energy and redox homeostasis. The study argues for sAC as a potential target in treating pathologies associated with AMPK downregulation.</description><subject>Adenylyl Cyclases - genetics</subject><subject>Adenylyl Cyclases - metabolism</subject><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinase Kinases</subject><subject>Animals</subject><subject>Bicarbonates</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cardiomyocytes</subject><subject>Cell Biology</subject><subject>Cell Physiological Phenomena</subject><subject>Cyclic AMP</subject><subject>Cyclic AMP - genetics</subject><subject>Cyclic AMP - metabolism</subject><subject>Depolarization</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - metabolism</subject><subject>Energy balance</subject><subject>Energy Metabolism - genetics</subject><subject>Guanine Nucleotide Exchange Factors - genetics</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Localization</subject><subject>Mammalian cells</subject><subject>Mitochondria</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - metabolism</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Original</subject><subject>Original Article</subject><subject>Oxidation-Reduction</subject><subject>Phosphates</subject><subject>Phosphorylation</subject><subject>Protein Kinases - genetics</subject><subject>Rats</subject><subject>Stimulation</subject><issn>1420-682X</issn><issn>1420-9071</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kUtv1DAUhSMEoqXwB1ggS2xYEPAricMGVRUvUQRCILGzHOcm48qxp7ZT4Z_Av8bTGcpjwcqW7nfO9fGpqocEPyMYd88jxpiIGpO-xow0tM63qmPCKa573JHbh3sr6Lej6l6MF4VuBG3vVkeMkI5S0h1XPz7DvFqVjHfIT-j0w6f3SOlkrkzKaMgo5S0ggpEawWWbLdJZWxXhBdLepWCG9VqaPEobQItJXm-8G4NRFg3GWz_np0iDtWVJQAFG_x0pNyJwEOaMNn4BH5OKJt6v7kzKRnhwOE-qr69ffTl7W59_fPPu7PS81g0nqRa8obTDg25HjsWEOdNsHHSjGeO0BUanvgPBYWiB9j0fFO3aSQysGRoA0QE7qV7ufbfrsMCoocRQVm6DWVTI0isj_544s5Gzv5KEENyUTysOTw4OwV-uEJNcTNxlVA78GiVlpOc9EwIX9PE_6IVfgyv5JKWs6Vvc8x1F95QOPsYA081rCJa7quW-almqltdVy1xEj_7McSP51W0B2B6IZeRmCL93_8f2J6pot2s</recordid><startdate>20191201</startdate><enddate>20191201</enddate><creator>Jayarajan, Vignesh</creator><creator>Appukuttan, Avinash</creator><creator>Aslam, Muhammad</creator><creator>Reusch, Peter</creator><creator>Regitz-Zagrosek, Vera</creator><creator>Ladilov, Yury</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PATMY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8529-4217</orcidid><orcidid>https://orcid.org/0000-0002-9836-8801</orcidid></search><sort><creationdate>20191201</creationdate><title>Regulation of AMPK activity by type 10 adenylyl cyclase: contribution to the mitochondrial biology, cellular redox and energy homeostasis</title><author>Jayarajan, Vignesh ; Appukuttan, Avinash ; Aslam, Muhammad ; Reusch, Peter ; Regitz-Zagrosek, Vera ; Ladilov, Yury</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-8452270bc6d408f043c3dbc5c33426e32f97e84eb6e2994ba276f8b35b5ee87e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adenylyl Cyclases - genetics</topic><topic>Adenylyl Cyclases - metabolism</topic><topic>AMP-activated protein kinase</topic><topic>AMP-Activated Protein Kinase Kinases</topic><topic>Animals</topic><topic>Bicarbonates</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cardiomyocytes</topic><topic>Cell Biology</topic><topic>Cell Physiological Phenomena</topic><topic>Cyclic AMP</topic><topic>Cyclic AMP - genetics</topic><topic>Cyclic AMP - metabolism</topic><topic>Depolarization</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - metabolism</topic><topic>Energy balance</topic><topic>Energy Metabolism - genetics</topic><topic>Guanine Nucleotide Exchange Factors - genetics</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Localization</topic><topic>Mammalian cells</topic><topic>Mitochondria</topic><topic>Mitochondria - genetics</topic><topic>Mitochondria - metabolism</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Original</topic><topic>Original Article</topic><topic>Oxidation-Reduction</topic><topic>Phosphates</topic><topic>Phosphorylation</topic><topic>Protein Kinases - genetics</topic><topic>Rats</topic><topic>Stimulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jayarajan, Vignesh</creatorcontrib><creatorcontrib>Appukuttan, Avinash</creatorcontrib><creatorcontrib>Aslam, Muhammad</creatorcontrib><creatorcontrib>Reusch, Peter</creatorcontrib><creatorcontrib>Regitz-Zagrosek, Vera</creatorcontrib><creatorcontrib>Ladilov, Yury</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cellular and molecular life sciences : CMLS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jayarajan, Vignesh</au><au>Appukuttan, Avinash</au><au>Aslam, Muhammad</au><au>Reusch, Peter</au><au>Regitz-Zagrosek, Vera</au><au>Ladilov, Yury</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of AMPK activity by type 10 adenylyl cyclase: contribution to the mitochondrial biology, cellular redox and energy homeostasis</atitle><jtitle>Cellular and molecular life sciences : CMLS</jtitle><stitle>Cell. Mol. Life Sci</stitle><addtitle>Cell Mol Life Sci</addtitle><date>2019-12-01</date><risdate>2019</risdate><volume>76</volume><issue>24</issue><spage>4945</spage><epage>4959</epage><pages>4945-4959</pages><issn>1420-682X</issn><eissn>1420-9071</eissn><abstract>The downregulation of AMP-activated protein kinase (AMPK) activity contributes to numerous pathologies. Recent reports suggest that the elevation of cellular cAMP promotes AMPK activity. However, the source of the cAMP pool that controls AMPK activity remains unknown. Mammalian cells possess two cAMP sources: membrane-bound adenylyl cyclase (tmAC) and intracellularly localized, type 10 soluble adenylyl cyclase (sAC). Due to the localization of sAC and AMPK in similar intracellular compartments, we hypothesized that sAC may control AMPK activity. In this study, sAC expression and activity were manipulated in H9C2 cells, adult rat cardiomyocytes or endothelial cells. sAC knockdown depleted the cellular cAMP content and decreased AMPK activity in an EPAC-dependent manner. Functionally, sAC knockdown reduced cellular ATP content, increased mitochondrial ROS formation and led to mitochondrial depolarization. Furthermore, sAC downregulation led to EPAC-dependent mitophagy disturbance, indicated by an increased mitochondrial mass and unaffected mitochondrial biogenesis. Consistently, sAC overexpression or stimulation with bicarbonate significantly increased AMPK activity and cellular ATP content. In contrast, tmAC inhibition or stimulation produced no effect on AMPK activity. Therefore, the sAC–EPAC axis may regulate basal and induced AMPK activity and support mitophagy, cellular energy and redox homeostasis. The study argues for sAC as a potential target in treating pathologies associated with AMPK downregulation.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>31172217</pmid><doi>10.1007/s00018-019-03152-y</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-8529-4217</orcidid><orcidid>https://orcid.org/0000-0002-9836-8801</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenylyl Cyclases - genetics Adenylyl Cyclases - metabolism AMP-activated protein kinase AMP-Activated Protein Kinase Kinases Animals Bicarbonates Biochemistry Biomedical and Life Sciences Biomedicine Cardiomyocytes Cell Biology Cell Physiological Phenomena Cyclic AMP Cyclic AMP - genetics Cyclic AMP - metabolism Depolarization Endothelial cells Endothelial Cells - metabolism Energy balance Energy Metabolism - genetics Guanine Nucleotide Exchange Factors - genetics Homeostasis Humans Kinases Life Sciences Localization Mammalian cells Mitochondria Mitochondria - genetics Mitochondria - metabolism Myocytes, Cardiac - metabolism Original Original Article Oxidation-Reduction Phosphates Phosphorylation Protein Kinases - genetics Rats Stimulation |
| title | Regulation of AMPK activity by type 10 adenylyl cyclase: contribution to the mitochondrial biology, cellular redox and energy homeostasis |
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