Abstract 8997: TRPM7 Mediates Hypomagnesemia-Induced Mitochondrial Dysfunction, Diastolic Heart Failure, and Death

Abstract

Introduction: Hypomagnesemia (HypoMg) induces mitochondrial dysfunction accompanied by disturbed Mg homeostasis in mouse hearts. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function located in the plasma membrane. Its upregulation has been observed in HypoMg. We investigated the role of TRPM7 in mitochondrial dysfunction mediated by HypoMg. Methods: Wild type (WT) C57BL/6J mice and transgenic mice with a K1646R mutation in the TRPM7 kinase domain (TRPM7 K1646R , with no kinase function) were fed with a low-Mg diet (HypoMg mice, 15-30 mg/kg Mg) or a normal Mg diet (control mice, 600 mg/kg Mg) for 6 weeks. Human cardiac RL-14 cells were cultured in a normal (with 0.81 mM MgSO 4 ) or a low-Mg medium (customized medium with 0.04 mM MgSO 4 ) for 48 h. TRPM7 knockdown was achieved by siRNA in RL-14 cells. Results: WT HypoMg mice showed significantly decreased serum Mg, diastolic dysfunction, increased mitochondrial ROS in isolated cardiomyocytes, increased TRPM7 mRNA and protein level, decreased ATP production and decreased total mitochondrial Mg content in heart tissues. TRPM7 K1646R mice on the low-Mg diet showed normal diastolic function, normal mitochondrial ROS levels in cardiomyocytes, and recovered ATP production and mitochondrial Mg content in hearts. Furthermore, TRPM7 K1646R prevent HypoMg-induced seizures and death (64.8% death in WT HypoMg mice). Hypomagnesemia in RL-14 cells resulted in increased mitochondrial ROS (1.77±0.08-fold of control, P<0.0001), which was suppressed to 0.86±0.04-fold of control by TRPM7 siRNA (25-30% TRPM7 reduction confirmed by RT-PCR and Western blot). Conclusions: HypoMg induces elevation of TRPM7 protein expression, and TRPM7 is involved in mitochondrial dysfunction, diastolic dysfunction, and death associated with HypoMg.