Journal
MITOCHONDRION
Volume 44, Issue -, Pages 41-52Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.mito.2017.12.011
Keywords
Free zinc; Mitochondria; Cardiomyocytes; Hyperglycemia; Heart failure; Fluorescence microscopy
Categories
Funding
- Scientific and Technological Research Council of Turkey (TUBITAK) [SBAG-113S466, SBAG-214S254]
- COST action [TD1304]
- Medical Research Council (UK) [MR/J0003042/1]
- Biotechnology and Biological Sciences Research Council (UK) [BB/J015873/1]
- Royal Society
- Wellcome Trust [WT098424A1A]
- European Cooperation in Science and Technology COST action STSM [TD1304]
- European Foundation for the Study of Diabetes
- BBSRC [BB/J015873/1] Funding Source: UKRI
- MRC [MR/K001981/1] Funding Source: UKRI
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Functional contribution of S(E)R-mitochondria coupling to normal cellular processes is crucial and any alteration in S(E)R-mitochondria axis may be responsible for the onset of diseases. Mitochondrial free Zn2+ level in cardiomyocytes ([Zn2+](Mit)) is lower comparison to either its cytosolic or S(E)R level under physiological condition. However, there is little information about distribution of Zn2+-transporters on mitochondria and role of Zn2+-dependent mitochondrial-function associated with [Zn2+](Mit). Since we recently have shown how hyperglycemia (HG)-induced changes in ZIP7 and ZnT7 contribute to Zn2+-transport across S(E)R and contribute to S(E)R-stress in the heart, herein, we hypothesized that these transporters can also be localized to mitochondria and affect the S(E)R-mitochondria coupling, and thereby contribute to cellular Zn2+-muffling between S(E)R-mitochondria in HG-cells. Mitochondrial localizations of ZIP7 and ZnT7 were demonstrated using fluorescence technique while they were confirmed in isolated mitochondrial fractions using biochemical analysis. Markedly decreased ZIP7 and increased ZnT7 levels were measured in isolated mitochondrial fractions from either HG- or doxorubicin, DOX (as positive control)-treated cardiomyocytes. Significantly increases in [Zn2+](Mit) and ROS production levels and depolarized mitochondrial membrane potential were also measured in HG cells. The expression levels of some key proteins, responsible for proper S(E)R-mitochondria coupling such as Mfn-1, Fis-1, OPAl, BAP31, STIM1 and PML in either HG- or DOX-cells were supported our above hypothesis, strongly. Overall, this study provides an important description about the role of ZIP7 and ZnT7, localized to both mitochondria and S(E)R and contribute to cellular Zn2+-muffling between cellular-compartments in HG or hypertrophic cardiomyocytes via affecting S(E)R-mitochondria coupling. Any alteration in this axis and/or cellular [Zn2+) may provide new insight for prevention/therapy of HF in diabetes and/or hypertrophy.
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