Enhancement of mitochondrial calcium uptake is cardioprotective against maladaptive hypertrophy by retrograde signaling uptuning Akt

被引：0

作者：

Zaglia, Tania ^{[1
,2
,3
]}

Campo, Antonio ^{[1
,2
]}

Moro, Nicola ^{[1
,2
]}

Di Mauro, Vittoria ^{[1
,2
]}

Borile, Giulia ^{[1
,2
]}

Menabo, Roberta ^{[1
]}

Antonucci, Salvatore ^{[1
]}

Poli, Laura ^{[1
]}

Campesan, Marika ^{[1
]}

Carullo, Pierluigi ^{[4
,5
]}

Martinazzi, Sara ^{[6
]}

Luciani, Giovanni B. ^{[6
]}

Hammer, Karin ^{[7
]}

Pesce, Paola ^{[8
]}

Bariani, Riccardo ^{[9
]}

Faggian, Giuseppe ^{[6
]}

Maier, Lars ^{[7
]}

Ventura, Laura ^{[10
]}

De Stefani, Diego ^{[1
]}

Mammucari, Cristina ^{[1
]}

Rizzuto, Rosario ^{[1
]}

Catalucci, Daniele ^{[4
,5
]}

Di Lisa, Fabio ^{[1
]}

Mongillo, Marco ^{[1
,2
,3
,11
]}

机构：

[1] Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy

[2] Veneto Inst Mol Med, I-35129 Padua, Italy

[3] Interdept Res Ctr Myol, I-35131 Padua, Italy

[4] Ist Ricovero & Cura Carattere Sci Humanitas Res Ho, I-20089 Milan, Italy

[5] CNR, Inst Genet & Biomed Res, Milan Unit, I-20138 Milan, Italy

[6] Univ Verona, Div Cardiac Surg, I-37126 Verona, Italy

[7] Univ Hosp Regensburg, Internal Med 2, D-93053 Regensburg, Germany

[8] Univ Padua, Dept Med, I-35128 Padua, Italy

[9] Univ Padua, Dept Cardiac Thorac Vasc Sci & Publ Hlth, I-35131 Padua, Italy

[10] Univ Padua, Dept Stat Sci, I-35121 Padua, Italy

[11] CNR, Inst Neurosci, Padua, Italy

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2025年 / 122卷 / 11期

关键词：

mitochondrial calcium uniporter; myocardial hypertrophy; beta adrenergic receptor; Akt; heart failure; INDUCED HEART-FAILURE; CARDIAC-HYPERTROPHY; MICE LACKING; IN-VIVO; OVERLOAD; MCU; TRANSITION; STRESS; OVEREXPRESSION; CARDIOMYOCYTES;

D O I：

10.1073/pnas.2402639122

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Regulation of mitochondrial Ca2+ uptake is critical in cardiac adaptation to chronic stressors. Abnormalities in Ca2+ handling, including mitochondrial uptake mechanisms, have been implicated in pathological heart hypertrophy. Enhancing mitochondrial Ca2+uniporter (MCU) expression has been suggested to interfere with maladaptive development of heart failure. Here, we addressed whether MCU modulation affects the cardiac response to pressure overload. MCU content was quantified in human and murine hearts at different phases of myocardial hypertrophy. Cardiac function/structure were analyzed after Transverse Aortic Constriction (TAC) in mice undergone viral-assisted overexpression or downregulation of MCU. In vitro and ex vivo assays determined the effect of MCU modulation on mitochondrial Ca2+ uptake, cellular phenotype and hypertrophic signaling. In human and murine hearts MCU levels increased in the adaptive phase of myocardial hypertrophy and declined in the failing stage. Consistently, modulation of MCU had a cell-autonomous effect in cardiomyocyte/heart adaptation to chronic overload. Indeed, upon TAC MCU-downregulation accelerated development of contractile dysfunction, interstitial fibrosis and heart failure. Conversely, MCU-overexpression prolonged the adaptive phase of hypertrophic response, as, in advanced stages upon TAC, hearts showed preserved contractility, absence of fibrosis and intact vascularization. In vitro and ex vivo analyses indicated that enhancement in mitochondrial Ca2+ uptake in cardiomyocytes entails "mitochondrion-to-cytoplasm" signals leading to ROS-mediated activation of Akt, which may explain the protective effects towards heart response to TAC. Enhanced mitochondrial Ca2+ uptake affects the compensatory response to pressure overload via retrograde mitochondrial-Ca2+/ROS/Akt signaling, thus uncovering a potentially targetable mechanism against maladaptive myocardial hypertrophy.

引用

页数：9

共 58 条

[1] The critical role of Akt in cardiovascular function
Abeyrathna, Prasanna
Su, Yunchao
[J]. VASCULAR PHARMACOLOGY, 2015, 74 : 38 - 48
[2] Mitochondrial Ca2þ Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure
Alves-Figueiredo, Hugo
Silva-Platas, Christian
Estrada, Manuel
Oropeza-Almazan, Yuriana
Ramos-Gonzalez, Martin
Bernal-Ramirez, Judith
Vazquez-Garza, Eduardo
Tellez, Armando
Salazar-Ramirez, Felipe
Mendez-Fernandez, Abraham
Galaz, Jose Luis
Lobos, Pedro
Youker, Keith
Lozano, Omar
Torre-Amione, Guillermo
Garcia-Rivas, Gerardo
[J]. JACC-BASIC TO TRANSLATIONAL SCIENCE, 2024, 9 (04): : 496 - 518
[3] Phosphoinositide 3-kinase signaling in the cellular response to oxidative stress
Barthel, A
Klotz, LO
[J]. BIOLOGICAL CHEMISTRY, 2005, 386 (03) : 207 - 216
[4] IGF1-PI3K-induced physiological cardiac hypertrophy: Implications for new heart failure therapies, biomarkers, and predicting cardiotoxicity
Bass-Stringer, Sebastian
Tai, Celeste M. K.
McMullen, Julie R.
[J]. JOURNAL OF SPORT AND HEALTH SCIENCE, 2021, 10 (06) : 637 - 647
[5] Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter
Baughman, Joshua M.
Perocchi, Fabiana
Girgis, Hany S.
Plovanich, Molly
Belcher-Timme, Casey A.
Sancak, Yasemin
Bao, X. Robert
Strittmatter, Laura
Goldberger, Olga
Bogorad, Roman L.
Koteliansky, Victor
Mootha, Vamsi K.
[J]. NATURE, 2011, 476 (7360) : 341 - U111
[6] Calcium Signaling and Reactive Oxygen Species in Mitochondria
Bertero, Edoardo
Maack, Christoph
[J]. CIRCULATION RESEARCH, 2018, 122 (10) : 1460 - 1478
[7] Cardiac-specific overexpression of E40K active Akt prevents pressure overload-induced heart failure in mice by increasing angiogenesis and reducing apoptosis
Ceci, M.
Gallo, P.
Santonastasi, M.
Grimaldi, S.
Latronico, M. V. G.
Pitisci, A.
Missol-Kolka, E.
Scimia, M. C.
Catalucci, D.
Hilfiker-Kleiner, D.
Condorelli, G.
[J]. CELL DEATH AND DIFFERENTIATION, 2007, 14 (05) : 1060 - 1062
[8] AKT signalling in the failing heart
Chaanine, Antoine H.
Hajjar, Roger J.
[J]. EUROPEAN JOURNAL OF HEART FAILURE, 2011, 13 (08) : 825 - 829
[9] The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure
Cluntun, Ahmad A.
Badolia, Rachit
Lettlova, Sandra
Parnell, K. Mark
Shankar, Thirupura S.
Diakos, Nikolaos A.
Olson, Kristofor A.
Taleb, Iosif
Tatum, Sean M.
Berg, Jordan A.
Cunningham, Corey N.
Van Ry, Tyler
Bott, Alex J.
Krokidi, Aspasia Thodou
Fogarty, Sarah
Skedros, Sophia
Swiatek, Wojciech I.
Yu, Xuejing
Luo, Bai
Merx, Shannon
Navankasattusas, Sutip
Cox, James E.
Ducker, Gregory S.
Holland, William L.
McKellar, Stephen H.
Rutter, Jared
Drakos, Stavros G.
[J]. CELL METABOLISM, 2021, 3 (03) : 629 - +
[10] Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice
Condorelli, G
Drusco, A
Stassi, G
Bellacosa, A
Roncarati, R
Iaccarino, G
Russo, MA
Gu, YS
Dalton, N
Chung, C
Latronico, MVG
Napoli, C
Sadoshima, J
Croce, CM
Ross, J
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (19) : 12333 - 12338

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