Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling

被引:33
作者
Gu, Linlin [1 ]
Surolia, Ranu [1 ]
Larson-Casey, Jennifer L. [1 ]
He, Chao [1 ]
Davis, Dana [1 ]
Kang, Jungsoon [1 ]
Antony, Veena B. [1 ]
Carter, A. Brent [1 ,2 ]
机构
[1] Univ Alabama Birmingham, Dept Med, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA
[2] Birmingham VAMC, Birmingham, AL 35233 USA
关键词
MITOCHONDRIAL CALCIUM UNIPORTER; ENDOPLASMIC-RETICULUM STRESS; FATTY-ACID OXIDATION; PULMONARY-FIBROSIS; BH4; DOMAIN; ALTERNATIVE ACTIVATION; CELL APOPTOSIS; BCL-2; INHIBITION; MACROPHAGES;
D O I
10.1038/s41418-021-00840-w
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mitochondrial calcium uniporter (MCU) regulates metabolic reprogramming in lung macrophages and the progression of pulmonary fibrosis. Fibrosis progression is associated with apoptosis resistance in lung macrophages; however, the mechanism(s) by which apoptosis resistance occurs is poorly understood. Here, we found a marked increase in mitochondrial B-cell lymphoma-2 (Bcl-2) in lung macrophages from subjects with idiopathic pulmonary fibrosis (IPF). Similar findings were seen in bleomycin-injured wild-type (WT) mice, whereas Bcl-2 was markedly decreased in mice expressing a dominant-negative mitochondrial calcium uniporter (DN-MCU). Carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme for fatty acid beta-oxidation, directly interacted with Bcl-2 by binding to its BH3 domain, which anchored Bcl-2 in the mitochondria to attenuate apoptosis. This interaction was dependent on Cpt1a activity. Lung macrophages from IPF subjects had a direct correlation between CPT1A and Bcl-2, whereas the absence of binding induced apoptosis. The deletion of Bcl-2 in macrophages protected mice from developing pulmonary fibrosis. Moreover, mice had resolution when Bcl-2 was deleted or was inhibited with ABT-199 after fibrosis was established. These observations implicate an interplay between macrophage fatty acid beta-oxidation, apoptosis resistance, and dysregulated fibrotic remodeling.
引用
收藏
页码:118 / 132
页数:15
相关论文
共 50 条
[1]   Proapoptotic bid is required for pulmonary fibrosis [J].
Budinger, GRS ;
Mutlu, GM ;
Eisenbart, J ;
Fuller, AC ;
Bellmeyer, AA ;
Baker, CM ;
Wilson, M ;
Ridge, K ;
Barrett, TA ;
Lee, VY ;
Chandel, NS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (12) :4604-4609
[2]   Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer [J].
Camarda, Roman ;
Zhou, Alicia Y. ;
Kohnz, Rebecca A. ;
Balakrishnan, Sanjeev ;
Mahieu, Celine ;
Anderton, Brittany ;
Eyob, Henok ;
Kajimura, Shingo ;
Tward, Aaron ;
Krings, Gregor ;
Nomura, Daniel K. ;
Goga, Andrei .
NATURE MEDICINE, 2016, 22 (04) :427-+
[3]   Selective Vulnerability of Cancer Cells by Inhibition of Ca2+ Transfer from Endoplasmic Reticulum to Mitochondria (vol 14, pg 2313, 2016) [J].
Cardenas, Cesar ;
Mueller, Marioly ;
McNeal, Andrew ;
Lovy, Alenka ;
Jana, Fabian ;
Bustos, Galdo ;
Urra, Felix ;
Smith, Natalia ;
Molgo, Jordi ;
Diehl, J. Alan ;
Ridky, Todd W. ;
Foskett, J. Kevin .
CELL REPORTS, 2016, 15 (01) :219-220
[4]   Transcriptional regulation of bcl-2 by nuclear factor κB and its significance in prostate cancer [J].
Catz, SD ;
Johnson, JL .
ONCOGENE, 2001, 20 (50) :7342-7351
[5]   PUMA cooperates with direct activator proteins to promote mitochondrial outer membrane permeabilization and apoptosis [J].
Chipuk, Jerry E. ;
Green, Douglas R. .
CELL CYCLE, 2009, 8 (17) :2692-2696
[6]   Bcl-xL promotes metastasis independent of its anti-apoptotic activity [J].
Choi, Soyoung ;
Chen, Zhengming ;
Tang, Laura H. ;
Fang, Yuanzhang ;
Shin, Sandra J. ;
Panarelli, Nicole C. ;
Chen, Yao-Tseng ;
Li, Yi ;
Jiang, Xuejun ;
Du, Yi-Chieh Nancy .
NATURE COMMUNICATIONS, 2016, 7
[7]   Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis [J].
Czabotar, Peter E. ;
Westphal, Dana ;
Dewson, Grant ;
Ma, Stephen ;
Hockings, Colin ;
Fairlie, W. Douglas ;
Lee, Erinna F. ;
Yao, Shenggen ;
Robin, Adeline Y. ;
Smith, Brian J. ;
Huang, David C. S. ;
Kluck, Ruth M. ;
Adams, Jerry M. ;
Colman, Peter M. .
CELL, 2013, 152 (03) :519-531
[8]   Context-dependent Bcl-2/Bak Interactions Regulate Lymphoid Cell Apoptosis [J].
Dai, Haiming ;
Meng, X. Wei ;
Lee, Sun-Hee ;
Schneider, Paula A. ;
Kaufmann, Scott H. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (27) :18311-18322
[9]   Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation [J].
Diwan, Abhinav ;
Wansapura, Janaka ;
Syed, Faisal M. ;
Matkovich, Scot J. ;
Lorenz, John N. ;
Dorn, Gerald W., II .
CIRCULATION, 2008, 117 (03) :396-404
[10]   Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction [J].
Docherty, NG ;
O'Sullivan, OE ;
Healy, DA ;
Fitzpatrick, JM ;
Watson, RWG .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2006, 290 (01) :F4-F13