TY  - JOUR
A1  - Seidlmayer, Lea K.
A1  - Mages, Christine
A1  - Berbner, Annette
A1  - Eder-Negrin, Petra
A1  - Arias-Loza, Paula Anahi
A1  - Kaspar, Mathias
A1  - Song, Moshi
A1  - Dorn, Gerald W.
A1  - Kohlhaas, Michael
A1  - Frantz, Stefan
A1  - Maack, Christoph
A1  - Gerull, Brenda
A1  - Dedkova, Elena N.
T1  - Mitofusin 2 is essential for IP3-mediated SR/Mitochondria metabolic feedback in ventricular myocytes
JF  - Frontiers in Physiology
N2  - Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP\(_3\)) by activating their membrane-bound receptors. We have previously demonstrated that IP\(_3\)-mediated sarcoplasmic reticulum (SR) Ca\(^{2+}\) release results in mitochondrial Ca\(^{2+}\) uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP\(_3\)-mediated SR/mitochondrial feedback in ventricular myocytes.
Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca\(^{2+}\) uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates.
Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca\(^{2+}\) uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca\(^{2+}\) uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca\(^{2+}\) uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca\(^{2+}\) uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca\(^{2+}\) uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions.
Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP\(_3\)-mediated SR Ca\(^{2+}\) release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP\(_3\)R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter).
KW  - mitofusin 2
KW  - IP3
KW  - SR/mitochondria metabolic feedback
KW  - mitochondrial mRyR1
KW  - ATP generation
KW  - endothelin-1
KW  - Mfn2 KO mice
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199141
SN  - 1664-042X
VL  - 10
IS  - 733
ER  -