The mitochondrial uniporter controls fight or flight heart rate increases
Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calci...
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| Veröffentlicht in: | Nature communications 2015-01, Vol.6 (1), p.6081-6081, Article 6081 |
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| creator | Wu, Yuejin Rasmussen, Tyler P. Koval, Olha M Joiner, Mei-ling A. Hall, Duane D. Chen, Biyi Luczak, Elizabeth D. Wang, Qiongling Rokita, Adam G. Wehrens, Xander H.T. Song, Long-Sheng Anderson, Mark E. |
| description | Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates calcium entry into the mitochondrial matrix to stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of a dominant-negative (DN) MCU. Here, we show that DN-MCU mice had normal resting heart rates but were incapable of physiological fight or flight heart rate acceleration. We found that MCU function was essential for rapidly increasing mitochondrial calcium in pacemaker cells and that MCU-enhanced oxidative phoshorylation was required to accelerate reloading of an intracellular calcium compartment before each heartbeat. Our findings show that MCU is necessary for complete physiological heart rate acceleration and suggest that MCU inhibition could reduce inappropriate heart rate increases without affecting resting heart rate.
Animals react to threats by increasing their heart rate. Wu
et al
. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate. |
| doi_str_mv | 10.1038/ncomms7081 |
| format | Article |
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Animals react to threats by increasing their heart rate. Wu
et al
. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms7081</identifier><identifier>PMID: 25603276</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/109 ; 13/44 ; 13/51 ; 13/89 ; 14 ; 14/1 ; 14/19 ; 14/34 ; 14/35 ; 14/63 ; 42 ; 42/35 ; 42/41 ; 42/44 ; 59 ; 631/443/592 ; 631/80/642/333/1465 ; 631/80/86/1999 ; 64 ; 64/110 ; 64/60 ; 692/308 ; 82 ; 9/10 ; 9/74 ; 96 ; Action Potentials ; Adenosine Triphosphate - chemistry ; Animals ; Biological Clocks ; Caffeine - chemistry ; Calcium - chemistry ; Calcium - metabolism ; Calcium Channels - physiology ; Echocardiography - methods ; Electrocardiography - methods ; Female ; Genes, Dominant ; Green Fluorescent Proteins - chemistry ; Heart - physiology ; Heart Rate - physiology ; Humanities and Social Sciences ; In Vitro Techniques ; Isoproterenol - chemistry ; Male ; Mice ; Mice, Transgenic ; Microscopy, Confocal ; Mitochondria - metabolism ; multidisciplinary ; Myocytes, Cardiac - cytology ; NAD - chemistry ; Perfusion ; Phosphorylation ; Science ; Science (multidisciplinary) ; Transgenes</subject><ispartof>Nature communications, 2015-01, Vol.6 (1), p.6081-6081, Article 6081</ispartof><rights>Springer Nature Limited 2015</rights><rights>Copyright Nature Publishing Group Jan 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-85b11b471dd32362702627f592967ad21d0aab9c71066ddc21a564666d7d95d03</citedby><cites>FETCH-LOGICAL-c508t-85b11b471dd32362702627f592967ad21d0aab9c71066ddc21a564666d7d95d03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398998/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398998/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/ncomms7081$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25603276$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Yuejin</creatorcontrib><creatorcontrib>Rasmussen, Tyler P.</creatorcontrib><creatorcontrib>Koval, Olha M</creatorcontrib><creatorcontrib>Joiner, Mei-ling A.</creatorcontrib><creatorcontrib>Hall, Duane D.</creatorcontrib><creatorcontrib>Chen, Biyi</creatorcontrib><creatorcontrib>Luczak, Elizabeth D.</creatorcontrib><creatorcontrib>Wang, Qiongling</creatorcontrib><creatorcontrib>Rokita, Adam G.</creatorcontrib><creatorcontrib>Wehrens, Xander H.T.</creatorcontrib><creatorcontrib>Song, Long-Sheng</creatorcontrib><creatorcontrib>Anderson, Mark E.</creatorcontrib><title>The mitochondrial uniporter controls fight or flight heart rate increases</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates calcium entry into the mitochondrial matrix to stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of a dominant-negative (DN) MCU. Here, we show that DN-MCU mice had normal resting heart rates but were incapable of physiological fight or flight heart rate acceleration. We found that MCU function was essential for rapidly increasing mitochondrial calcium in pacemaker cells and that MCU-enhanced oxidative phoshorylation was required to accelerate reloading of an intracellular calcium compartment before each heartbeat. Our findings show that MCU is necessary for complete physiological heart rate acceleration and suggest that MCU inhibition could reduce inappropriate heart rate increases without affecting resting heart rate.
Animals react to threats by increasing their heart rate. Wu
et al
. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate.</description><subject>13</subject><subject>13/1</subject><subject>13/109</subject><subject>13/44</subject><subject>13/51</subject><subject>13/89</subject><subject>14</subject><subject>14/1</subject><subject>14/19</subject><subject>14/34</subject><subject>14/35</subject><subject>14/63</subject><subject>42</subject><subject>42/35</subject><subject>42/41</subject><subject>42/44</subject><subject>59</subject><subject>631/443/592</subject><subject>631/80/642/333/1465</subject><subject>631/80/86/1999</subject><subject>64</subject><subject>64/110</subject><subject>64/60</subject><subject>692/308</subject><subject>82</subject><subject>9/10</subject><subject>9/74</subject><subject>96</subject><subject>Action Potentials</subject><subject>Adenosine Triphosphate - chemistry</subject><subject>Animals</subject><subject>Biological Clocks</subject><subject>Caffeine - chemistry</subject><subject>Calcium - chemistry</subject><subject>Calcium - metabolism</subject><subject>Calcium Channels - physiology</subject><subject>Echocardiography - methods</subject><subject>Electrocardiography - methods</subject><subject>Female</subject><subject>Genes, Dominant</subject><subject>Green Fluorescent Proteins - chemistry</subject><subject>Heart - physiology</subject><subject>Heart Rate - physiology</subject><subject>Humanities and Social Sciences</subject><subject>In Vitro Techniques</subject><subject>Isoproterenol - chemistry</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microscopy, Confocal</subject><subject>Mitochondria - metabolism</subject><subject>multidisciplinary</subject><subject>Myocytes, Cardiac - cytology</subject><subject>NAD - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Wu, Yuejin</au><au>Rasmussen, Tyler P.</au><au>Koval, Olha M</au><au>Joiner, Mei-ling A.</au><au>Hall, Duane D.</au><au>Chen, Biyi</au><au>Luczak, Elizabeth D.</au><au>Wang, Qiongling</au><au>Rokita, Adam G.</au><au>Wehrens, Xander H.T.</au><au>Song, Long-Sheng</au><au>Anderson, Mark E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The mitochondrial uniporter controls fight or flight heart rate increases</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2015-01-20</date><risdate>2015</risdate><volume>6</volume><issue>1</issue><spage>6081</spage><epage>6081</epage><pages>6081-6081</pages><artnum>6081</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates calcium entry into the mitochondrial matrix to stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of a dominant-negative (DN) MCU. Here, we show that DN-MCU mice had normal resting heart rates but were incapable of physiological fight or flight heart rate acceleration. We found that MCU function was essential for rapidly increasing mitochondrial calcium in pacemaker cells and that MCU-enhanced oxidative phoshorylation was required to accelerate reloading of an intracellular calcium compartment before each heartbeat. Our findings show that MCU is necessary for complete physiological heart rate acceleration and suggest that MCU inhibition could reduce inappropriate heart rate increases without affecting resting heart rate.
Animals react to threats by increasing their heart rate. Wu
et al
. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25603276</pmid><doi>10.1038/ncomms7081</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/1 13/109 13/44 13/51 13/89 14 14/1 14/19 14/34 14/35 14/63 42 42/35 42/41 42/44 59 631/443/592 631/80/642/333/1465 631/80/86/1999 64 64/110 64/60 692/308 82 9/10 9/74 96 Action Potentials Adenosine Triphosphate - chemistry Animals Biological Clocks Caffeine - chemistry Calcium - chemistry Calcium - metabolism Calcium Channels - physiology Echocardiography - methods Electrocardiography - methods Female Genes, Dominant Green Fluorescent Proteins - chemistry Heart - physiology Heart Rate - physiology Humanities and Social Sciences In Vitro Techniques Isoproterenol - chemistry Male Mice Mice, Transgenic Microscopy, Confocal Mitochondria - metabolism multidisciplinary Myocytes, Cardiac - cytology NAD - chemistry Perfusion Phosphorylation Science Science (multidisciplinary) Transgenes |
| title | The mitochondrial uniporter controls fight or flight heart rate increases |
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