Mitochondrion-Targeting Fluorescence Probe via Reduction Induced

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Mitochondrion-Targeting Fluorescence Probe via Reduction Induced Charge Transfer for Fast Methionine Sulfoxide Reductases Imaging Mei-Hao Xiang, Hui Huang, Xian-Jun Liu, Zong-Xuan Tong, Chun-Xia Zhang, Fenglin Wang, Ru-Qin Yu, and Jian-Hui Jiang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b00383 • Publication Date (Web): 10 Apr 2019 Downloaded from http://pubs.acs.org on April 10, 2019

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Analytical Chemistry

Mitochondrion-Targeting Fluorescence Probe via Reduction Induced Charge Transfer for Fast Methionine Sulfoxide Reductases Imaging Mei-Hao Xiang†, Hui Huang†, Xian-Jun Liu, Zong-Xuan Tong, Chun-Xia Zhang, Fenglin Wang*, Ru-Qin Yu and Jian-Hui Jiang* State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China ABSTRACT: Methionine sulfoxide reductases (Msrs) play essential roles in maintaining mitochondrial function and are recognized as potential therapeutic targets. However, current probes for Msrs fail to target mitochondria and exhibit relatively slow response and limited sensitivity. Here we develop a novel turn-on fluorescence probe that facilitates imaging of mitochondrial Msrs in living cells. The probe is constructed by conjugating a methyl phenyl sulfoxide, a mimic Msrs substrate, to an electron-withdrawing hydrophobic cation, methylpyridinium. The probe of acceptor-acceptor structure is initially non-emissive. Msrs catalyzed reduction of sulfoxide to sulfide generated a fluorophore of distinct donor-acceptor structure. The probe is demonstrated to exhibit high sensitivity, fast response and high selectivity towards MsrA in vitro. Furthermore, the probe is successfully introduced to detect and image Msrs in living cells with excellent mitochondrialtargeting capability. Moreover, the probe also reveals decreased Msrs activity in a cellular Parkinson’s disease model. Our probe affords a powerful tool for detecting and visualizing mitochondrial Msrs in living cells.

Mitochondrial redox state is essential for mitochondrial function and cellular status.1-3 Mitochondrial redox homeostasis is delicately regulated by various antioxidant systems.4-6 As a crucial antioxidant defense system, methionine sulfoxide reductases (Msrs) are revealed to play indispensable roles in regulating mitochondrial function.7-9 Msrs, mainly consistent of methionine sulfoxide reductase A (MsrA) and B (MsrB), can stereospecifically reduce methionine sulfoxide to the corresponding isomers with the aid of electron donors (dithiothreitol (DTT) in vitro and thioredoxin in vivo).10-12 Abnormal levels of Msrs are closely associated with aging and neurodegenerative diseases including Parkinson’s disesase.13-15 Therefore, it is highly desirable to detect and image Msrs activity in mitochondria. Small molecule based fluorescence probes with analytes activated signal have been introduced to detect various proteins and enzyme activities in living cells.16-19 In this context, several turn-on fluorescence probes have been developed to facilitate visualization of Msrs activity. The first activatable fluorescence probe for Msrs was designed to image MsrA activity in E. coli, using dipyrromethene as the fluorophore and (S)-sulfoxide as the substrate.20 By screening a library of substrates, a turn-on fluorescence probe based on coumarin was obtained for imaging Msrs in mammalian cells.21 However, it displayed relatively slow response (~6 h). The response time and sensitivity can be improved with modified coumarin derivatives.22 To our knowledge, there were no fluorescence probes for imaging mitochondrial Msrs in living cells. It is still quite challenging to develop a highly sensitive and rapid

response fluorescence probe for detection and visualizing Msrs in mitochondria. Here we report the first mitochondria-targeting fluoresce probe which enabled highly sensitive and rapid imaging of mitochondrial Msrs. The catalytic pocket of Msrs was mainly localized on the protein surface which is relatively small and confined.23-25 Inspired by this structure, we design several fluorescent probes for Msrs with relatively small and extended shape by conjugating methyl phenyl sufoxide (MS), a well-known Msrs substrate, with different small electron with-drawing cationic moieties (Scheme 1a). We envision that a fluorescence probe with small size would better fit the catalytic pocket and possess high affinity, while Msrs-catalyzed reduction of the electron withdrawing sulfoxide to an electron donating sulfide could generate turn on fluorescence probes for Msrs based on intramoleuclar charge transfer (ICT) (Scheme 1b). Motivated by this rationale, we design four probes by conjugating MS with 1,4-dimethylpyridium (MSP1), 1,2-dimethylpyridium (MSP2), 1,4dimethylquinolinium (MSQ1) and 1,2dimethylquinolinium (MSQ2), respectively. These probes are initially non-emissive due to the acceptor-acceptor electronic structure. Fluorescence signal is switched on upon Msrs-mediated reduction of the electron withdrawing sulfoxide to an electron donating sulfide, generating fluorophores of distinct donor-acceptor structure and large Stokes shift. Among them, MSP1 is demonstrated to exhibit high sensitivity, fast response and high specificity toward MsrA in vitro. Meanwhile, the hydrophobic methylpyridium endows the probe with

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excellent mitochondrial targeting ability. Furthermore, MSP1 is capable of detecting and imaging mitochondrial Msrs in living cells. Moreover, MSP1 is successfully introduced to detect reduced Msrs activity in a cellular model for Parkinson’s disease. To our knowledge, this is the first mitochondrial-targeting fluorescent probe that enables detection and imaging of mitochondrial Msrs in living cells.

(Figure 1a).21 Moreover, incubation of MSP1 with HeLa cell lysates led to an evident increase in fluorescence, which was dramatically decreased for cell lysates pretreated with the inhibitor (Figure S14). These results implied that Msrs in the cell lysates could reduce MSP1 with activated fluorescence, which could be specifically inhibited by the inhibitor. All together, these results demonstrated that MSP1 could be specifically activated by Msrs.

Scheme 1. (a) Structures of probes for Msrs. (b) Illustration of fluorescence turn-on mechanism for Msrs detection.

Figure 1. (a) Fluorescence spectra of MSP1. MSP1 (10 μM) (I), MSP1 (10 μM) + MsrA (3.0 μg/mL) (II), MSP1 (10 μM) + MsrA (3.0 μg/mL) + DMSO (0.05%) (III) in Tris-HCl buffers (25 mM, pH 7.4) at 37 °C for 1 h. (b) Fluorescence spectra of MSP1 (10 μM) to various concentrations of MsrA in Tris-HCl buffers (25 mM, pH 7.4) at 37 °C for 1 h. (c) Selectivity of MSP1 (10 μM) to different relevant substances in Tris-HCl buffers (25 mM, pH 7.4) at 37 °C for 1 h. (d) Fluorescence kinetic curves of MSP1 to different concentrations of MsrA. MSP1 (10 μM) (I), MSP1 (10 μM) + MsrA (0.5, 1.0, 3.0, 5.0 μg/mL) (II-V) in Tris-HCl buffers (25 mM, pH 7.4) at 37 °C for 4800 s.

Four probes were first synthesized and thoroughly characterized with MS, 1H NMR, and 13C NMR, respectively (Scheme S1, Figures S1-S12). We then set on selecting potential fluorescence probes for Msrs using DTT as the electron donor in vitro. All the probes exhibited negligible fluorescence enhancement upon DTT treatment, indicating that DTT did not reduce the sulfoxide moiety (Table S1). The fluorescence responses of the four probes were then studied upon incubation with DTT and MrsA. The fluorescence enhancements for MSP1 and MSP2 were ~35 and 1.5 fold, respectively, meanwhile, those for MSQ1 and MSQ2 were ~4.5 and 1.7 fold, respectively (Table S1). The greater fluorescence enhancements for MSP1 and MSQ1 with para substitution might be due to their better fit with the deep catalytic pocket.23-25 Therefore, MSP1 was chosen for further studies owing to its largest signal enhancement. The response of MSP1 towards Msrs was then investigated, using MsrA as a model in vitro. MSP1 had a maximal absorption at 337 nm and was non-emissive (ΦF = 0.2%) (Figure 1a, Figure S13). In contrast, the absorption maximum was red shifted to 385 nm with ~35-fold enhancement in fluorescence at 547 nm upon incubation with MsrA. This bathochromic shift and dramatic fluorescence enhancement were ascribed to MsrA mediated sulfoxide reduction, generating a fluorophore with distinct ICT (ΦF = 10%). In contrast, the fluorescence emission was dramatically attenuated for MsrA pretreated with 0.05% dimethyl sulfoxide (DMSO), an Msrs inhibitor

The sensitivity of MSP1 towards MrsA was then determined by incubating MSP1 with different concentrations of MrsA (0 - 4.0 μg/mL), the fluorescence intensity exhibited a dynamic increase with a saturated response at 2.0 μg/mL (Figure 1b). The fluorescence intensities at 547 nm were linearly proportional to the concentrations of MrsA in the range of 0.1 - 1.0 μg/mL, with an estimated detection limit of 0.01 μg/ml (0.35 nM) (Figure S15). This sensitivity was much higher than the existing fluorescence probes, suggesting that MSP1 afforded a highly sensitive method for MrsA detection.20-22 The superior sensitivity might be attributed to its excellent affinity towards MsrA, producing a fluorophore with a large Stokes shift. A closer investigation revealed that the Michaelis constant Km for MsrA was ~24 μM (Figure S16), much smaller than the previous reported values (~120 μM).21 Such a small Michaelis constant implied a strong affinity between MSP1 and MsrA, resulting in improved sensitivity. Together, these results demonstrated our probe was an ideal substrate for MsrA, preserving its outstanding enzymatic activity. The selectivity of MSP1 to MsrA was then investigated by incubating MSP1 with various potential interfering species including DTT, tris(2-carboxyethyl)phosphine (TCEP), 2

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Analytical Chemistry glutathione (GSH), cysteine (Cys), homocysteine (Hcy), vitamin c, bovine serum albumin (BSA), nitroreductase (NTR), NAD(P)H: quinone oxidoreductase isozyme 1 (NQO1), thioredoxin reductase (TrxR). All these species showed negligible fluorescence activation, similar to that of the blank (Figure 1c). On the contrary, the fluorescence was dramatically turned on upon addition of MsrA. These results indicated that MSP1 was highly selective towards Msrs. Furthermore, the study of pH and temperature effect on the catalytic activity of MsrA revealed MSP1 was stable in different pH (5.0-9.0) with an optimal catalytic efficiency at pH 7.0 and 37 oC (Figures S17 and S18). These results implied that MSP1 could detect Msrs in physiological conditions. Moreover, the response time of MSP1 towards MsrA was recorded by incubating MSP1 with different concentrations of MsrA. The fluorescence signals rapidly increased upon addition of MsrA (Figure 1d). Particularly, the fluorescence intensity reached plateau in 6 min for MSP1 treated with 5.0 μg/mL MsrA (174 nM), which was much faster than the previous fluorescence probes.20-22 All together, these results suggested that MSP1 could detect Msrs activity with high selectivity and fast response in physiological conditions.

Proliferation Assay kit. Both cells had over 90% viability for concentrations of MSP1 up to 500 μM upon 24 h incubation, suggesting that MSP1 was of great biocompatibility. (Figure S19). Then, HeLa cells were pretreated with MSP1 before differential interference contrast (DIC) and fluorescence images were obtained. There were bright fluorescence signals for cells incubated with MSP1 as compared to the cells without MSP1 (Figure 3, a1-b1, Figure S20). In contrast, there were very dim fluorescence signals for cells sequentially treated with the inhibitor DMSO and MSP1 (Figure 3, c1, Figure S20). These results indicated that MSP1 could be specifically reduced by intracellular Msrs with activated fluorescence signals. Furthermore, Z-stacked images revealed that the probe were inside the cells with activated signal (Figure S21). Similarly, HEK-293T cells incubated with MSP1 also exhibited strong fluorescence signal which was dramatically inhibited by DMSO (Figure S22). Together, these results implied that MSP1 could image and unveil Msrs activity with high specificity in living cells.

Figure 2. (a) HPLC profiles of MSP1 (50 μM) (I), MSP1 (50 μM) reacted with MsrA (5.0 μg/mL) (II) in Tris-HCl buffers (25 mM, pH 7.4) at 37 °C for 1 h and rMSP1 (10 μM) (III). (b) HR-ESI-MS spectrum of the reaction product of MSP1 (10 μM) and MsrA (3.0 μg/mL) in Tris-HCl buffers (25 mM, pH 7.4) at 37 °C for 1 h.

To verify the reaction mechanism, the reaction products of MSP1 and MsrA were analyzed with HPLC and HR-ESIMS, respectively. HPLC chromatogram revealed the products had two substances with retention times of 5.259 min and 7.368 min, corresponding to the residue MSP1 and its reduction product rMSP1, respectively (Figure 2a). The conversion rate was estimated to be 42%, suggesting that the S isomer of MSP1 could be reduced by MsrA with good efficiency. Furthermore, MS analysis revealed that reaction products emerged a new peak corresponding to rMSP1 (calcd for C15H16NS+ [M-H]-, m/z=242.0998, found 242.1078), besides the peak of MSP1 (calcd for C15H16NOS+ [M-H]-, m/z=258.0947, found 258.1031) (Figure 2b). These results demonstrated that MSP1 could be reduced by MsrA, generating a fluorophore, consistent with our proposed reaction mechanism. We then investigated its ability to image Msrs activity in living cells using both HeLa and HEK-293T cell lines. The cytotoxicity of MSP1 was first evaluated with a Cell

Figure 3. Fluorescence and DIC overlay images and colocalization assay of HeLa cells. (a1) cells without MSP1. (b1) cells treated with MSP1 (100 μM) for 4 h. (c1) cells sequentially treated DMSO (1%) and MSP1 (100 μM) for 4 h. (a2-c2) Cells sequentially treated with MSP1 for 4 h and then Mito-Tracker red (100 nM) for 15 min. (a3-c3) Cells pretreated by MSP1 (100 μM) for 4 h and then Lyso-Tracker red (100 nM) for 15 min. Scale bar = 10 μm.

The intracellular localization of MSP1 was then investigated with colocalization assay. HeLa cells were costained with MitoTracker red and LysoTracker red to stain mitochondria and lysosomes, respectively. Fluorescence signals from MSP1 and MitoTracker red correlated well with a Pearson correlation coefficient (PCC) of 0.89 (Figure 3, a2-c2, Figure S23). However, the PCC was only 0.40 between the fluorescence signal of MSP1 and that 3



of Lyso-Tracker red (Figure 3, a3-c3). Similar results were also obtained for HEK-293T cells, with PCCs of 0.85 and 0.36 for mitochondria and lysosomes, respectively (Figure S24). These results demonstrated that our probe could specifically respond to mitochondrial Msrs activity. We then introduced MSP1 to image Msrs activity in PC12, a typical cell line for constructing Parkinson’s disease (PD) model. First, the cytotoxicity of MSP1 towards PC12 also revealed MSP1 was highly biocompatible, exhibiting over 90% viability upon incubation of over 500 μM MSP1 (Figure S25). Then, cellular PD models were established using 6hydroxydopamine (6-OHDA) as a neurotoxin according to literature.21,26 Confocal fluorescence images revealed that the fluorescence signals of cells decreased as the cells treated with 0, 35 and 70 μM of 6-OHDA (Figure 4, Figure S26), which might be attributed to 6-OHDA induced oxidative stress. Furthermore, colocalization assay indicated that MSP1 was localized in mitochondrial with a PCC of ~0.75, suggesting that our probe could image mitochondrial Msrs activity in 6-OHDA treated cells (Figure S27). Moreover, the activity of Msrs in cell lysates also gradually decreased for cells treated with 35 μM and 70 μM of 6-OHDA as compared to control cells (Figure S28), consistent with literature results.21 The protein levels of MsrA did not have significant changes after being treated with 6-OHDA (Figure S29). Together, these results revealed decreased Msrs activity in a cellular PD model. MSP1 6-OHDA (a1)

(b1)

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great potential in investigating mitochondrial Msrs-related complications in living cells. Future work includes developing activatable probes with longer wavelengths for selectively detection of MrsA and MrsB.

ASSOCIATED CONTENT Supporting Information Experimental methods including synthetic procedures, compounds characterizations, in vitro assays, cell culture and fluorescence imaging as well as additional figures. These materials are available free of charge on the ACS Publications website. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author*Fax: +86-731-88821916. * Email: [email protected]; Email: [email protected].

ORCID Jian-Hui Jiang: 0000-0003-1594-4023

Author Contributions †M.X.

and H.H. contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This study was financially supported by the National Natural Science Foundation of China (21527810, 91753107 and 21705041).

REFERENCES (a2)

(b2)

(c2)

(d2)

Figure 4. Fluorescence and DIC overlay images of PC12 cells. (a1, a2) Cells without MSP1. (b1, b2) Cells treated with MSP1 (100 μM) for 4 h. (c1, c2) Cells treated with 6-OHDA (35 μM) for 16 h and then MSP1 (100 μM) for 4 h. (d1, d2) Cells treated with 6-OHDA (70 μM) for 16 h and then MSP1 (100 μM) for 4 h. Scale bar = 20 μm.

In conclusion, we have developed a novel turn-on fluorescence probe for detection and imaging mitochondrial Msrs in living cells. The probe was initially non-emissive, but exhibited intense fluorescence signals upon Msrs-catalyzed reduction. Our probe was demonstrated to have high sensitivity, fast response and high selectivity towards MsrA activity in vitro. Furthermore, it was successfully applied to detect and visualize Msrs in both HeLa and HEK-293T cells with high specificity. Moreover, its ability to target mitochondria and image Msrs in both cell lines was also demonstrated. In addition, our probe was successfully introduced to detect decreased mitochondrial Msrs activity in cellular Parkinson’s disease. We believe our probe would hold

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