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http://purl.uniprot.org/citations/22777004http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/22777004http://www.w3.org/2000/01/rdf-schema#comment"

Rationale

Mitochondrial Ca(2+) uptake is essential for the bioenergetic feedback response through stimulation of Krebs cycle dehydrogenases. Close association of mitochondria to the sarcoplasmic reticulum (SR) may explain efficient mitochondrial Ca(2+) uptake despite low Ca(2+) affinity of the mitochondrial Ca(2+) uniporter. However, the existence of such mitochondrial Ca(2+) microdomains and their functional role are presently unresolved. Mitofusin (Mfn) 1 and 2 mediate mitochondrial outer membrane fusion, whereas Mfn2 but not Mfn1 tethers endoplasmic reticulum to mitochondria in noncardiac cells.

Objective

To elucidate roles for Mfn1 and 2 in SR-mitochondrial tethering, Ca(2+) signaling, and bioenergetic regulation in cardiac myocytes.

Methods and results

Fruit fly heart tubes deficient of the Drosophila Mfn ortholog MARF had increased contraction-associated and caffeine-sensitive Ca(2+) release, suggesting a role for Mfn in SR Ca(2+) handling. Whereas cardiac-specific Mfn1 ablation had no effects on murine heart function or Ca(2+) cycling, Mfn2 deficiency decreased cardiomyocyte SR-mitochondrial contact length by 30% and reduced the content of SR-associated proteins in mitochondria-associated membranes. This was associated with decreased mitochondrial Ca(2+) uptake (despite unchanged mitochondrial membrane potential) but increased steady-state and caffeine-induced SR Ca(2+) release. Accordingly, Ca(2+)-induced stimulation of Krebs cycle dehydrogenases during β-adrenergic stimulation was hampered in Mfn2-KO but not Mfn1-KO myocytes, evidenced by oxidation of the redox states of NAD(P)H/NAD(P)(+) and FADH(2)/FAD.

Conclusions

Physical tethering of SR and mitochondria via Mfn2 is essential for normal interorganelle Ca(2+) signaling in the myocardium, consistent with a requirement for SR-mitochondrial Ca(2+) signaling through microdomains in the cardiomyocyte bioenergetic feedback response to physiological stress."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.org/dc/terms/identifier"doi:10.1161/circresaha.112.266585"xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Chen Y."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Liu Y."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Wang W."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Nerbonne J.M."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Maack C."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Kohlhaas M."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Csordas G."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Dorn G.W."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Bergem S."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Csordas N."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Jowdy C."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Meiser M."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/author"Schneider T.G."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/date"2012"xsd:gYear
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/name"Circ Res"xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/pages"863-875"xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/title"Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca(2+) crosstalk."xsd:string
http://purl.uniprot.org/citations/22777004http://purl.uniprot.org/core/volume"111"xsd:string
http://purl.uniprot.org/citations/22777004http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/22777004
http://purl.uniprot.org/citations/22777004http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/22777004
http://purl.uniprot.org/uniprot/#_D3Z5P8-mappedCitation-22777004http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/22777004
http://purl.uniprot.org/uniprot/#_A2A7Y8-mappedCitation-22777004http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/22777004
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