Adenosine monophosphate deaminase in the endoplasmic reticulum–mitochondria interface promotes mitochondrial Ca2+ overload in type 2 diabetes rat hearts. Issue 4 (23rd February 2023)

• Record Type: Journal Article
• Authors: Osanami, Arata; Sato, Tatsuya; Toda, Yuki; Shimizu, Masaki; Kuno, Atsushi; Kouzu, Hidemichi; Yano, Toshiyuki; Ohwada, Wataru; Ogawa, Toshifumi; Miura, Tetsuji; Tanno, Masaya
• Is Part Of: Journal of diabetes investigation. Volume 14:Issue 4(2023)
• Page Start: 560
• Page End: 569
• Publication Date: 2023-02-23
• Subjects: Adenosine monophosphate deaminase -- Diabetic cardiomyopathy -- Mitochondria‐associated endoplasmic reticulum membrane; Diabetes -- Periodicals; Diabetes -- Research -- Periodicals; Diabetes Mellitus -- Periodicals; 616.462005
• DOI: 10.1111/jdi.13982
• Languages: English
• ISSNs: 2040-1116

Abstract

Abstract: Aims/Introduction: We previously showed that upregulation of myocardial adenosine monophosphate deaminase (AMPD) is associated with pressure overload‐induced diastolic dysfunction in type 2 diabetes hearts. Here, we examined involvement of AMPD localized in the endoplasmic reticulum–mitochondria interface in mitochondrial Ca 2+ overload and its pathological significance. Materials and Methods: We used type 2 diabetes Otsuka Long–Evans Tokushima Fatty rats (OLETF) and non‐diabetes Long–Evans Tokushima Otsuka Fatty rats (LETO) as well as AMPD3‐overexpressing H9c2 cells and human embryonic kidney 293 cells. Results: OLETF, but not LETO, showed diastolic dysfunction under the condition of phenylephrine‐induced pressure overload. The levels of 90‐kDa AMPD3 in outer mitochondrial membranes/endoplasmic reticulum and mitochondria‐associated endoplasmic reticulum membrane (MAM) fractions were significantly higher in OLETF than in LETO. The area of the MAM quantified by electron microscopic analysis was 57% larger, mitochondrial Ca 2+ level under the condition of pressure overload was 47% higher and Ca 2+ retention capacity in MAM‐containing crude mitochondria isolated before the pressure overloading was 21% lower in OLETF than in LETO (all P ‐values <0.05). Transfection of FLAG‐AMPD3 in cells resulted in significant enlargement of the MAM area, and impairment in pyruvate/malate‐driven adenosine triphosphate‐stimulated and uncoupler‐stimulated mitochondrial respiration compared with those in control cells. Conclusions: The findings suggest that 90‐kDa AMPD3 localized in the endoplasmic reticulum–mitochondria interface promotes formation of the MAM, inducing mitochondrial Ca 2+ overload and dysfunction in type 2 diabetes hearts. Abstract : Adenosine monophosphate deaminase 3 in the endoplasmic reticulum–mitochondria interface is upregulated in diabetic rat hearts. Adenosine monophosphate deaminase 3 in the endoplasmic reticulum–mitochondria interface promotes the formation of mitochondria‐associated endoplasmic reticulum membrane, mitochondrial Ca 2+ overload and mitochondrial respiratory dysfunction, contributing to the development of diabetic cardiomyopathy.