MMP-2 is localized to the mitochondria-associated membrane of the heart

被引:40
作者
Hughes, Bryan G. [1 ,2 ,4 ]
Fan, Xiaohu [1 ,2 ,4 ]
Cho, Woo Jung [3 ]
Schulz, Richard [1 ,2 ,4 ]
机构
[1] Univ Alberta, Dept Pediat, Edmonton, AB, Canada
[2] Univ Alberta, Dept Pharmacol, Edmonton, AB, Canada
[3] Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB, Canada
[4] Univ Alberta, Mazankowski Alberta Heart Inst, Cardiovasc Res Ctr, Edmonton, AB, Canada
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2014年 / 306卷 / 05期
基金
加拿大健康研究院;
关键词
matrix metalloproteinase 2; mitochondria-associated membrane; mitochondria; calreticulin; ISCHEMIA-REPERFUSION INJURY; MATRIX-METALLOPROTEINASE INHIBITORS; ENDOPLASMIC-RETICULUM; SUBCELLULAR-LOCALIZATION; TARGETING SEQUENCES; CALRETICULIN; PROTEIN; PEROXYNITRITE; ACTIVATION; PREDICTION;
D O I
10.1152/ajpheart.00909.2013
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Matrix metalloproteinase-2 (MMP-2) has been extensively studied in the context of extracellular matrix remodeling but is also localized within cells and can be activated by prooxidants to proteolyze specific intercellular targets. Although there are reports of MMP-2 in mitochondria, a critical source of cellular oxidative stress, these studies did not take into account the presence within their preparations of the mitochondria-associated membrane (MAM), a subdomain of the endoplasmic reticulum (ER). We hypothesized that MMP-2 is situated in the MAM and therefore investigated its subcellular distribution between mitochondria and the MAM. Immunogold electron microscopy revealed MMP-2 localized in mitochondria of heart sections from mice. In contrast, immunofluorescence analysis of an MMP-2: HaloTag fusion protein expressed in HL-1 cardiomyocytes showed an ER-like distribution, with greater colocalization with an ER marker (protein disulfide isomerase) relative to the mitochondrial marker, MitoTracker red. Although MMP-2 protein and enzymatic activity were present in crude mitochondrial fractions, once these were separated into purified mitochondria and MAM, MMP-2 was principally associated with the latter. Thus, although mitochondria may contain minimal levels of MMP-2, the majority of MMP-2 previously identified as "mitochondrial" is in fact associated with the MAM. We also found that calreticulin, an ER-and MAM-resident Ca2+ handling protein and chaperone, could be proteolyzed by MMP-2 in vitro. MAM-localized MMP-2 could therefore potentially impact mitochondrial function by affecting ER-mitochondrial Ca2+ signaling via its proteolysis of calreticulin.
引用
收藏
页码:H764 / H770
页数:7
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