Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy
•Knockdown of the mitochondrial protein Opa1 evokes enhanced mitochondrial Ca2+ uptake.•In humans defect of OPA1 gene induces autosomal dominant optic atrophy (ADOA).•We studied mitochondrial Ca2+ metabolism in fibroblasts of ADOA patients.•The symptoms of visual malfunction correlated with mitochon...
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| Veröffentlicht in: | Cell calcium (Edinburgh) 2015-01, Vol.57 (1), p.49-55 |
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| creator | Fülöp, László Rajki, Anikó Maka, Erika Molnár, Mária Judit Spät, András |
| description | •Knockdown of the mitochondrial protein Opa1 evokes enhanced mitochondrial Ca2+ uptake.•In humans defect of OPA1 gene induces autosomal dominant optic atrophy (ADOA).•We studied mitochondrial Ca2+ metabolism in fibroblasts of ADOA patients.•The symptoms of visual malfunction correlated with mitochondrial Ca2+ uptake.•Enhanced mitochondrial Ca2+ uptake may contribute to the progress of the disease.
The most frequent form of hereditary blindness, autosomal dominant optic atrophy (ADOA), is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca2+ uptake (Fülöp et al., 2011). Therefore we studied mitochondrial Ca2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell–inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca2+ signals. The present data indicate that enhanced mitochondrial Ca2+ uptake is a pathogenetic factor in the progress of ADOA. |
| doi_str_mv | 10.1016/j.ceca.2014.11.008 |
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The most frequent form of hereditary blindness, autosomal dominant optic atrophy (ADOA), is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca2+ uptake (Fülöp et al., 2011). Therefore we studied mitochondrial Ca2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell–inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca2+ signals. The present data indicate that enhanced mitochondrial Ca2+ uptake is a pathogenetic factor in the progress of ADOA.</description><identifier>ISSN: 0143-4160</identifier><identifier>EISSN: 1532-1991</identifier><identifier>DOI: 10.1016/j.ceca.2014.11.008</identifier><identifier>PMID: 25533789</identifier><language>eng</language><publisher>Netherlands: Elsevier Ltd</publisher><subject>Adult ; Advanced Basic Science ; Apoptosis ; Bradykinin - pharmacology ; Calcium - metabolism ; Calcium ion ; Calcium Signaling - drug effects ; Cells, Cultured ; Child ; Evoked Potentials - drug effects ; Female ; Fibroblast ; Fibroblasts - cytology ; Fibroblasts - metabolism ; Ganglion cell ; GTP Phosphohydrolases - genetics ; Humans ; Introns ; Male ; Microscopy, Confocal ; Mitochondria ; Mitochondria - metabolism ; OPA1 ; Optic atrophy ; Optic Atrophy, Autosomal Dominant - metabolism ; Optic Atrophy, Autosomal Dominant - pathology ; Oxidative Stress ; Pedigree ; Polymorphism, Single Nucleotide ; Severity of Illness Index</subject><ispartof>Cell calcium (Edinburgh), 2015-01, Vol.57 (1), p.49-55</ispartof><rights>Elsevier Ltd</rights><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-e9738c2833f51ee161155b06a470cbb996cf0dccffc62bf7d65499e0ac7fb2073</citedby><cites>FETCH-LOGICAL-c418t-e9738c2833f51ee161155b06a470cbb996cf0dccffc62bf7d65499e0ac7fb2073</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0143416014001961$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25533789$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fülöp, László</creatorcontrib><creatorcontrib>Rajki, Anikó</creatorcontrib><creatorcontrib>Maka, Erika</creatorcontrib><creatorcontrib>Molnár, Mária Judit</creatorcontrib><creatorcontrib>Spät, András</creatorcontrib><title>Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy</title><title>Cell calcium (Edinburgh)</title><addtitle>Cell Calcium</addtitle><description>•Knockdown of the mitochondrial protein Opa1 evokes enhanced mitochondrial Ca2+ uptake.•In humans defect of OPA1 gene induces autosomal dominant optic atrophy (ADOA).•We studied mitochondrial Ca2+ metabolism in fibroblasts of ADOA patients.•The symptoms of visual malfunction correlated with mitochondrial Ca2+ uptake.•Enhanced mitochondrial Ca2+ uptake may contribute to the progress of the disease.
The most frequent form of hereditary blindness, autosomal dominant optic atrophy (ADOA), is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca2+ uptake (Fülöp et al., 2011). Therefore we studied mitochondrial Ca2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell–inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca2+ signals. The present data indicate that enhanced mitochondrial Ca2+ uptake is a pathogenetic factor in the progress of ADOA.</description><subject>Adult</subject><subject>Advanced Basic Science</subject><subject>Apoptosis</subject><subject>Bradykinin - pharmacology</subject><subject>Calcium - metabolism</subject><subject>Calcium ion</subject><subject>Calcium Signaling - drug effects</subject><subject>Cells, Cultured</subject><subject>Child</subject><subject>Evoked Potentials - drug effects</subject><subject>Female</subject><subject>Fibroblast</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - metabolism</subject><subject>Ganglion cell</subject><subject>GTP Phosphohydrolases - genetics</subject><subject>Humans</subject><subject>Introns</subject><subject>Male</subject><subject>Microscopy, Confocal</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>OPA1</subject><subject>Optic atrophy</subject><subject>Optic Atrophy, Autosomal Dominant - metabolism</subject><subject>Optic Atrophy, Autosomal Dominant - pathology</subject><subject>Oxidative Stress</subject><subject>Pedigree</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Severity of Illness Index</subject><issn>0143-4160</issn><issn>1532-1991</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkkGL1TAUhYMozpvRP-BCshSkNTdp0wZEGB46CiMu1HVI01teOm1Tk3Sk_96WN7pwIa4ul_udszjnEvICWA4M5Js-t2hNzhkUOUDOWP2IHKAUPAOl4DE5bAeRFSDZBbmMsWeMKVHBU3LBy1KIqlYH0n92yduTn9rgzECPhr-my5zMHVLrQ8DBJIz0p0snmk5II95jcGmlvjvv6zgnP0bqJmqW5KMfN5fWj24yU6J-Ts5Sk4KfT-sz8qQzQ8TnD_OKfP_w_tvxY3b75ebT8fo2swXUKUNVidryWoiuBESQAGXZMGmKitmmUUrajrXWdp2VvOmqVpaFUsiMrbqGs0pckVdn3zn4HwvGpEcXLQ6DmdAvUYOUNS9qAew_0JKLuqwL2FB-Rm3wMQbs9BzcaMKqgem9Dt3rvQ6916EB9FbHJnr54L80I7Z_JL_z34C3ZwC3QO4dBh2tw8li6wLapFvv_u3_7i-5HdzkrBnucMXY-yVMW9QadOSa6a_7Q-z_AAVjoCSIX2GUsUM</recordid><startdate>20150101</startdate><enddate>20150101</enddate><creator>Fülöp, László</creator><creator>Rajki, Anikó</creator><creator>Maka, Erika</creator><creator>Molnár, Mária Judit</creator><creator>Spät, András</creator><general>Elsevier Ltd</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>7X8</scope><scope>7QP</scope></search><sort><creationdate>20150101</creationdate><title>Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy</title><author>Fülöp, László ; Rajki, Anikó ; Maka, Erika ; Molnár, Mária Judit ; Spät, András</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-e9738c2833f51ee161155b06a470cbb996cf0dccffc62bf7d65499e0ac7fb2073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Advanced Basic Science</topic><topic>Apoptosis</topic><topic>Bradykinin - pharmacology</topic><topic>Calcium - metabolism</topic><topic>Calcium ion</topic><topic>Calcium Signaling - drug effects</topic><topic>Cells, Cultured</topic><topic>Child</topic><topic>Evoked Potentials - drug effects</topic><topic>Female</topic><topic>Fibroblast</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - metabolism</topic><topic>Ganglion cell</topic><topic>GTP Phosphohydrolases - genetics</topic><topic>Humans</topic><topic>Introns</topic><topic>Male</topic><topic>Microscopy, Confocal</topic><topic>Mitochondria</topic><topic>Mitochondria - metabolism</topic><topic>OPA1</topic><topic>Optic atrophy</topic><topic>Optic Atrophy, Autosomal Dominant - metabolism</topic><topic>Optic Atrophy, Autosomal Dominant - pathology</topic><topic>Oxidative Stress</topic><topic>Pedigree</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Severity of Illness Index</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fülöp, László</creatorcontrib><creatorcontrib>Rajki, Anikó</creatorcontrib><creatorcontrib>Maka, Erika</creatorcontrib><creatorcontrib>Molnár, Mária Judit</creatorcontrib><creatorcontrib>Spät, András</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Calcium & Calcified Tissue Abstracts</collection><jtitle>Cell calcium (Edinburgh)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fülöp, László</au><au>Rajki, Anikó</au><au>Maka, Erika</au><au>Molnár, Mária Judit</au><au>Spät, András</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy</atitle><jtitle>Cell calcium (Edinburgh)</jtitle><addtitle>Cell Calcium</addtitle><date>2015-01-01</date><risdate>2015</risdate><volume>57</volume><issue>1</issue><spage>49</spage><epage>55</epage><pages>49-55</pages><issn>0143-4160</issn><eissn>1532-1991</eissn><abstract>•Knockdown of the mitochondrial protein Opa1 evokes enhanced mitochondrial Ca2+ uptake.•In humans defect of OPA1 gene induces autosomal dominant optic atrophy (ADOA).•We studied mitochondrial Ca2+ metabolism in fibroblasts of ADOA patients.•The symptoms of visual malfunction correlated with mitochondrial Ca2+ uptake.•Enhanced mitochondrial Ca2+ uptake may contribute to the progress of the disease.
The most frequent form of hereditary blindness, autosomal dominant optic atrophy (ADOA), is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca2+ uptake (Fülöp et al., 2011). Therefore we studied mitochondrial Ca2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell–inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca2+ signals. The present data indicate that enhanced mitochondrial Ca2+ uptake is a pathogenetic factor in the progress of ADOA.</abstract><cop>Netherlands</cop><pub>Elsevier Ltd</pub><pmid>25533789</pmid><doi>10.1016/j.ceca.2014.11.008</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Advanced Basic Science Apoptosis Bradykinin - pharmacology Calcium - metabolism Calcium ion Calcium Signaling - drug effects Cells, Cultured Child Evoked Potentials - drug effects Female Fibroblast Fibroblasts - cytology Fibroblasts - metabolism Ganglion cell GTP Phosphohydrolases - genetics Humans Introns Male Microscopy, Confocal Mitochondria Mitochondria - metabolism OPA1 Optic atrophy Optic Atrophy, Autosomal Dominant - metabolism Optic Atrophy, Autosomal Dominant - pathology Oxidative Stress Pedigree Polymorphism, Single Nucleotide Severity of Illness Index |
| title | Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy |
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