Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk

Yun Chen, György Csordás, Casey Jowdy, Timothy G. Schneider, Norbert Csordás, Wei Wang, Yingqiu Liu, Michael Kohlhaas, Maxie Meiser, Stefanie Bergem, Jeanne M. Nerbonne, Gerald W. Dorn, Christoph Maack

Research output: Contribution to journalArticle

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Abstract

RATIONALE: Mitochondrial Ca 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 uptake despite low Ca affinity of the mitochondrial Ca uniporter. However, the existence of such mitochondrial Ca 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 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 release, suggesting a role for Mfn in SR Ca handling. Whereas cardiac-specific Mfn1 ablation had no effects on murine heart function or Ca 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 uptake (despite unchanged mitochondrial membrane potential) but increased steady-state and caffeine-induced SR Ca release. Accordingly, Ca-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 FADH2/FAD. CONCLUSIONS: Physical tethering of SR and mitochondria via Mfn2 is essential for normal interorganelle Ca signaling in the myocardium, consistent with a requirement for SR-mitochondrial Ca signaling through microdomains in the cardiomyocyte bioenergetic feedback response to physiological stress.

Original languageEnglish (US)
Pages (from-to)863-875
Number of pages13
JournalCirculation Research
Volume111
Issue number7
DOIs
StatePublished - Sep 14 2012
Externally publishedYes

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Sarcoplasmic Reticulum
Cardiac Myocytes
Energy Metabolism
Mitochondria
Citric Acid Cycle
Caffeine
NAD
Oxidoreductases
Physiological Stress
Membrane Fusion
Flavin-Adenine Dinucleotide
Mitochondrial Membrane Potential
Diptera
Endoplasmic Reticulum
Adrenergic Agents
Muscle Cells
Drosophila
Oxidation-Reduction
Fruit
Myocardium

Keywords

  • calcium signaling
  • cardiac metabolism
  • excitation-contraction coupling
  • mitochondria
  • redox

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk. / Chen, Yun; Csordás, György; Jowdy, Casey; Schneider, Timothy G.; Csordás, Norbert; Wang, Wei; Liu, Yingqiu; Kohlhaas, Michael; Meiser, Maxie; Bergem, Stefanie; Nerbonne, Jeanne M.; Dorn, Gerald W.; Maack, Christoph.

In: Circulation Research, Vol. 111, No. 7, 14.09.2012, p. 863-875.

Research output: Contribution to journalArticle

Chen, Y, Csordás, G, Jowdy, C, Schneider, TG, Csordás, N, Wang, W, Liu, Y, Kohlhaas, M, Meiser, M, Bergem, S, Nerbonne, JM, Dorn, GW & Maack, C 2012, 'Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk', Circulation Research, vol. 111, no. 7, pp. 863-875. https://doi.org/10.1161/CIRCRESAHA.112.266585
Chen, Yun ; Csordás, György ; Jowdy, Casey ; Schneider, Timothy G. ; Csordás, Norbert ; Wang, Wei ; Liu, Yingqiu ; Kohlhaas, Michael ; Meiser, Maxie ; Bergem, Stefanie ; Nerbonne, Jeanne M. ; Dorn, Gerald W. ; Maack, Christoph. / Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk. In: Circulation Research. 2012 ; Vol. 111, No. 7. pp. 863-875.
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AU - Chen, Yun

AU - Csordás, György

AU - Jowdy, Casey

AU - Schneider, Timothy G.

AU - Csordás, Norbert

AU - Wang, Wei

AU - Liu, Yingqiu

AU - Kohlhaas, Michael

AU - Meiser, Maxie

AU - Bergem, Stefanie

AU - Nerbonne, Jeanne M.

AU - Dorn, Gerald W.

AU - Maack, Christoph

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N2 - RATIONALE: Mitochondrial Ca 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 uptake despite low Ca affinity of the mitochondrial Ca uniporter. However, the existence of such mitochondrial Ca 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 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 release, suggesting a role for Mfn in SR Ca handling. Whereas cardiac-specific Mfn1 ablation had no effects on murine heart function or Ca 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 uptake (despite unchanged mitochondrial membrane potential) but increased steady-state and caffeine-induced SR Ca release. Accordingly, Ca-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 FADH2/FAD. CONCLUSIONS: Physical tethering of SR and mitochondria via Mfn2 is essential for normal interorganelle Ca signaling in the myocardium, consistent with a requirement for SR-mitochondrial Ca signaling through microdomains in the cardiomyocyte bioenergetic feedback response to physiological stress.

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KW - excitation-contraction coupling

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KW - redox

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