TY - JOUR
T1 - Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk
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
PY - 2012/9/14
Y1 - 2012/9/14
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.
AB - 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.
KW - calcium signaling
KW - cardiac metabolism
KW - excitation-contraction coupling
KW - mitochondria
KW - redox
UR - http://www.scopus.com/inward/record.url?scp=84866530818&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.112.266585
DO - 10.1161/CIRCRESAHA.112.266585
M3 - Article
C2 - 22777004
AN - SCOPUS:84866530818
SN - 0009-7330
VL - 111
SP - 863
EP - 875
JO - Circulation research
JF - Circulation research
IS - 7
ER -