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Article | Open Access

Luteolin, a common flavone in vegetables, acts as a hormetin possessing neurotrophic function: signaling mediated by inducing mitochondrial stress

Alex Xiong Gao^{^a^,^b}, Tracy Chenxi Xia^{^a^,^b}, Maggie Suisui Guo^{^a^,^b}, Gary Kawing Yuen^{^a^,^b}, Kevin Qiyun Wu^{^a^,^b}, Tina Tingxia Dong^{^a^,^b}, Karl Wah-Keung Tsim^{^a^,^b}()

a

Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong 999077, China

b

Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Shenzhen 518000, China

Peer review under responsibility of Beijing Academy of Food Sciences.

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Abstract

This study aims to uncover the hormetic process of luteolin, a common dietary flavone, in neuronal cells through its role in inducing mitochondrial stress. In rat pheochromocytoma PC12 cells, luteolin at low concentrations caused a mild and reversible loss of mitochondrial membrane potential (MMP), while high concentrations of luteolin triggered intense and sustained depolarization of MMP. The MMP disturbance was shown to have a close association with the trophic and/or toxic effects triggered by luteolin; because the common mitochondrial uncouplers shared similar bi-phase dose-response on cell viability, as that of luteolin. Along with the induced MMP pertubation, luteolin triggered the development of autophagy and mitophagy, as determined by mCherry-GFP-LC3B tandem protein, and by the co-localization of mitochondrial/lysosomal staining. Subsequent application of autophagy inhibitors in the cultures blocked the luteolin-induced neurotrophic activities and sensitized the cells to be less resistant to luteolin-mediated cytotoxicity. Other flavonoids also displayed similar properties in the cultures, indicating that these compounds act as hormetic pharmacological inducers that stimulate cells to become more resilient and adapt to threats. This study provides a unifying mechanistic explanation for the neuro-beneficial effects of luteolin and other flavonoids.

Keywords

Flavonoids Hormesis Mitochondrial membrane potential Autophagy Mitophagy

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Food Science and Human Wellness

Volume 14 Issue 2,
February 2025

Article number: 9250035

DOI: 10.26599/FSHW.2024.9250035

Cite this article:

Gao AX, Xia TC, Guo MS, et al. Luteolin, a common flavone in vegetables, acts as a hormetin possessing neurotrophic function: signaling mediated by inducing mitochondrial stress. Food Science and Human Wellness, 2025, 14(2): 9250035. https://doi.org/10.26599/FSHW.2024.9250035

Fig. 1 Luteolin acutely depolarizes the MMP of PC12 cells. (A) PC12 cells were loaded with TMRE (20 nmol/L), followed by luteolin treatment at different concentrations for 15 min. Images were taken by the fluorescence microscope (left), and the MMP change was analyzed (right). (B) After loading PC12 cells with JC-1 dye (1 μg/mL), cultures were washed and exposed to luteolin or mitochondrial uncouplers, i.e. FCCP, BAM15, and 2,4-DNP, for 15 min. The fluorescence ratio of red to green (corresponding to MMP) was detected by microplate reader. (C) MMP of PC12 cells was assayed by TMRE after an indicated period of luteolin/FCCP treatment. (D) The effects of luteolin on MMP of different cells were assayed by JC-1 method. Values are expressed as percentage of control in mean ± SD, n = 3−4.
Fig. 2 Luteolin and uncouplers exert similar neurotrophic activities. (A) PC12 cells were administered with different concentrations of luteolin or uncouplers for 24 h, in serum-free condition. Cell viability was analyzed by MTT method. (B) Cells were transfected with pCRE-Luc, pARE-Luc, and pNF200-Luc, followed by treatment of luteolin or mitochondrial uncouplers for 24 h in DMEM (with 1% FBS and 1% horse serum). Luciferase activity was measured in equalized by the amount of protein. Values are expressed as percentage of control, or folds of change, in mean ± SD, n = 4.
Fig. 3 Luteolin and uncouplers possess similar neuroprotective activities. (A) PC12 cells were administered with different concentrations of tBHP for 1 h, in serum-free condition. Cell viability was analyzed by MTT method. (B) PC12 cells were pre-conditioned with luteolin, FCCP, or BAM15 for 12 h. The cultures were washed and then replenished with fresh DMEM dissolved with tBHP (1 mmol/L). Following 1 h of oxidative stimulation, the cell viability was tested by MTT method. (C) Cultured astrocytes were treated with luteolin (1, 5, 20 μmol/L), FCCP (1, 2, 5 μmol/L), or 2,4-DNP (5, 10, 20 μmol/L) in DMEM (with 10% FBS) for 3 h, followed by LPS (20 ng/mL) treatment for 12 h. The expression levels of IL-1β, IL-6, and TNF-α, were tested by real-time PCR. Dexamethasone (Dex) at 10 μmol/L was used as a positive control. Values are expressed as percentage of control, or folds of change, in mean ± SD, n = 4. * P < 0.05 against untreated control or tBHP/LPS-treated group.
Fig. 4 Luteolin induces mitochondrial stress. PC12 cells were treated with luteolin for 24 h in serum-free conditions. Subsequently, the stainings of DHE, MitoSOX, and PI/DAPI were used to identify intracellular ROS, mitochondrial ROS, and cell death, respectively. (A) Representative images were shown, and (B) results in (A) were quantitatively analyzed. FCCP served as a positive control. (C) Cells were treated with 50 μmol/L of luteolin for indicated time, followed by PBS wash and replacement of fresh DMEM medium. 24 h later, cell viability was tested to assess the resulting toxicity. (D) Upon 3 h of luteolin treatment at 5 or 50 μmol/L, mitochondrial bioenergetic status of PC12 cells was assayed by Seahorse Analyzer. Three respiratory chain inhibitors were given to the culture at indicated time points, and the instant OCR was recorded three times after each action. The normalized OCR change with time was shown. (E) Three mitochondrial bioenergetic parameters, i.e. basal respiration, ATP-linked respiration, and maximal respiration, were quantified by analyzing the OCR in (D). Values are expressed as the fold of change, or as percentage of control, or normalized OCR, in mean ± SD, n = 3−4. * P < 0.05 against untreated control.
Fig. 5 Luteolin induces autophagy and mitophagy. (A) Three hours after luteolin induction, cells were harvested for the expressions of SQSTM1/p62 (~62 kDa) and LC3A/B (~14, ~16 kDa) (left). Protein quantification (right) was in reference to β-actin (~45 kDa). Rapamycin (RAP) was used as a positive control. (B) Cells were transfected with pCMV-mCherry-GFP-LC3B construct for the expression of LC3 tandem protein. Afterward, luteolin was administrated for 3 h, and confocal imaging was performed to visualize the GFP/RFP fluorescent puncta (upper). Quantification result was shown (lower). (C) Upon luteolin treatment, the dyes of mitochondria and lysosome were loaded into the cultures. The occurrence of mitochondrion/lysosome co-localization was imaged by confocal microscopy (upper). Quantification of the co-localization was shown (lower). Values are expressed as percentage of control, or folds of change, in mean ± SD, n = 3−4. * P < 0.05 against control.
Fig. 6 Autophagy inhibitors block the neurotrophic functions of luteolin. (A) PC12 cells were pre-treated with autophagy inhibitors, CQ (5 μmol/L) or BafA1 (0.1 μmol/L), for 1 h, prior to 3 h of luteolin incubation. MMP was tested by TMRE staining. (B) After pre-incubation of autophagy inhibitors, the luteolin and FCCP were introduced to cells, and cell viability was tested after 24 h. (C) PC12 cells were transfected with reporter constructs, i.e. pCRE-Luc, pARE-Luc, pNF200-Luc. Following 1 h of CQ administration, luteolin at 5 μmol/L was applied to cells, and luciferase assay was performed 24 h later. Values are expressed as percentage of control, or folds of change, in mean ± SD, n = 4. * P < 0.05 against the treatment in the absence of CQ.
Fig. 7 Luetolin analogues induce mitohormesis. (A) The effects of representative flavones, i.e. apigenin, chrysin, wogonin, and baicalein, on MMP of PC12 cells were assayed by JC-1 method. (B) The depolarizating effects of flavones at 20 μmol/L on MMP of SH-SY5Y cells and cortical neurons. (C) Flavones affected the MMP of rat astrocytes, microglia, and RAW264.7 cells. (D) The depolarization mediated by flavone compounds in Caco-2, HepG2 cells, and HUVEC. (E) Flavones were given to PC12 cells for 24 h, then the cell viability was tested by MTT method. (F) Upon CQ (5 μmol/L) pre-treatment, flavones (50 μmol/L) and mitochondrial uncouplers (1, 2, and 50 μmol/L, respectively for BAM15, FCCP, and 2,4-DNP) were given to cells. Cell viability was assessed subsequent to 24 h of cultivation. Values are expressed as percentage of control, or percentage of change, in mean ± SD, n = 3−6.
Fig. 8 Structure of flavonoids determines the depolarizing capability. (A) Different flavonoids at 20 μmol/L were employed to PC12 cells for 15 min of treatment, the MMP was determined by JC-1 staining. (B) PC12 cells were exposed to 20 μmol/L of luteolin and its three glucosides for 15 min. DPBA was loaded to the cultures for another 15 min of incubation. The accumulation of flavonoids in cells was imaged by fluorescent microscopy. Quercetin (20 μmol/L) served as a positive control. (C) PC12 cells were transfected with reporter constructs, pCRE-Luc, pARE-Luc, and pNF200-Luc. Subsequent to 24 h treatment of luteolin aglycone/glucosides, luciferase assay was conducted. L-4’-G, luteolin 4’-glucoside; L-5-G, luteolin 5-glucoside; L-7-G, luteolin 7-glucoside. Values are expressed as percentage of control, or folds of change, in mean ± SD, n = 4.

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