title: Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca(2+) crosstalk.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: Yun
authors: Y
authors: Chen
authors: György
authors: G
authors: Csordás
authors: Casey
authors: C
authors: Jowdy
authors: Timothy G
authors: TG
authors: Schneider
authors: Norbert
authors: N
authors: Csordás
authors: Wei
authors: W
authors: Wang
authors: Yingqiu
authors: Y
authors: Liu
authors: Michael
authors: M
authors: Kohlhaas
authors: Maxie
authors: M
authors: Meiser
authors: Stefanie
authors: S
authors: Bergem
authors: Jeanne M
authors: JM
authors: Nerbonne
authors: Gerald W
authors: GW
authors: Dorn
authors: Christoph
authors: C
authors: Maack
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology*; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; C527117:Marf protein, Drosophila; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; D002118:Calcium