Review ArticleModulation of mitochondrial functions by the indirect antioxidant sulforaphane: A seemingly contradictory dual role and an integrative hypothesis
Graphical abstract
Introduction
Sulforaphane (SFN), or 1-isothiocyanate-(4R)-(methylsulfinyl)butane (Fig. 1), is a natural compound obtained from cruciferous vegetables. In broccoli, SFN is the major inducer of phase II detoxifying enzymes and is one of the most characterized isothiocyanates [1], [2]. SFN is considered an indirect antioxidant because of its potent activity as an inducer of cytoprotective proteins and its negligible scavenging capacity [3], [4]. The most documented target for SFN is the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling path (Fig. 1), a pathway that plays a significant role in protecting cells against endogenous and exogenous stresses [5], [6]. However, other molecular targets have been recognized [7] (see next sections) and, at present, relationships with the Keap1/Nrf2/ARE pathway have not been established for most of them. Nrf2 is a basic leucine-zipper-like transcription factor that resides in the cytoplasm until an increase in oxidative stress causes its translocation to the nucleus. Once there, Nrf2 heterodimerizes to other basic leucine-zipper proteins (Jun and small Maf family) and binds to the cis-acting enhancer sequence, the ARE, present in promoters of genes that code for detoxifying proteins [6], [8]. It has been proposed that the Nrf2 nuclear translocation induced by SFN could be mediated by two general mechanisms (Fig. 1): (i) disruption of the cytoplasmic association between Nrf2 and the thiol-rich repressor protein Keap1, mediated by the formation of SFN–Keap1 thionoacyl adducts that modify the Keap1 conformation and enable Nrf2 stabilization and nuclear translocation [9], [10], [11], and (ii) modulation of various kinase-mediated signaling pathways including mitogen-activated protein kinases, such as extracellular signal-regulated kinase (ERK) 1/2, c-Jun NH2-terminal kinase (JNK), and p38, and the activation routes of phosphoinositide 3-kinase (PI3K)–protein kinase B/Akt and protein kinase C (PKC), which can directly phosphorylate Nrf2 or targets that regulate Nrf2 at other levels [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23].
From the simplest point of view, if enzymes such as catalase or superoxide dismutase (SOD), which are in mitochondrial fractions, are regulated by Nrf2 [24], [25], [26], then an effect on mitochondrial function by SFN could be expected. In 2000, 8 years after the appearance of SFN on the investigative scene, the first work involving changes in mitochondrial parameters mediated by SFN was reported [27]. At the beginning SFN attracted much attention because of its anticarcinogenic properties mediated by inhibition of phase I and induction of phase II enzymes [28], [29]. The first sightings of SFN as a modulator of mitochondrial functions were associated with its antiproliferative properties and the induction of intrinsic apoptosis in cancer cells (see Table 1). However, with the advent of numerous experimental trials in cultured cells and animals using SFN as a cytoprotective agent against oxidative damage (as an antioxidant) [29], the mitochondrial-protective role of SFN was arising. Here, we review the reports that have implicated the biological and physiological effects of SFN in the induction of changes in mitochondrial functions and signaling, from cultured tumor cell models of cytotoxicity to animal models of cytoprotection against toxic or ischemia/reperfusion insults. We try to integrate these seemingly contradictory mitochondrial effects: those that appear damaging to the mitochondrion, making it dysfunctional and bringing the cell to an apoptotic death, and on the other side, those that seem protective, preserving the mitochondrial function when cells are exposed to mitochondria-targeted toxicants, or even that appear to increase mitochondrial activity per se.
Section snippets
Apoptosis induction through a mitochondria-dependent pathway
Apoptosis is a genetically controlled form of cell death, organized into discrete signaling pathways that induce proteolytic and nucleolytic activities. Those activities drive the cell to death through a defined sequence of morphological events [30]. There are two major apoptotic pathways responding to different signals: (i) an extrinsic or death-receptor pathway, which is activated from outside the cell by ligation of transmembrane death receptors with their corresponding ligands, and (ii) an
Preservation of mitochondrial function and integrity against toxic and ischemic insult and apoptosis inhibition
The physiological functions of mitochondria include ATP production, ROS generation and detoxification, apoptosis involvement, cytoplasmic and mitochondrial matrix calcium regulation, metabolite synthesis and catabolism, and the transport of the organelles themselves to correct locations within the cell. Abnormality in any of these processes can be termed as mitochondrial dysfunction [71]. Table 2 shows trials involving cytoprotective effects of SFN mediated by prevention of mitochondrial
Induction of mitochondrial biogenesis by SFN
Since Piantadosi and colleagues [92] reported that mitochondrial biogenesis was regulated via Nrf2, the hypothesis that SFN induced such mechanism became quite acceptable. This working group reported that the 5′ untranslated region for nuclear respiratory factor-1 (NRF-1; required for mitochondrial biogenesis) contains ARE promoter motifs for Nrf2. Indeed, nuclear translocation of Nrf2 was followed by NRF-1 induction and mitochondrial biogenesis, rescuing mice from doxorubicin-induced
More than a hormetic biphasic behavior
SFN has been proposed to be a phytochemical with hormetic features because of its capacity to induce an adaptive response to a moderate stress in cells and organisms through induction of cytoprotective phase II proteins [96], [97], [98]. In addition, SFN has shown biphasic dose responses in cells. For example, Zanichelli et al. [99] showed evidence that low concentrations of SFN (0.25–5 μM) promote human mesenchymal stem cell (noncancer cells) proliferation and protect them from apoptosis and
Conclusions
Taking together all the evidence cited for either antiproliferative or cytoprotective effects induced by SFN, regulation of mitochondrial redox balance and phase II enzyme expression, control of Δψm, changes in the family of Bcl-2 homologs, regulation of proapoptotic protein release from mitochondria, activation/inactivation of caspases, preservation of mitochondrial respiratory complex activity, oxygen consumption and bioenergetics, regulation of MPT pore opening, modulation of some kinase
Acknowledgments
This work was supported by PAPIIT (Grant IN210713) and CONACYT (Grants 167949 and 129838). We are grateful to Luis Fernando Granados-Castro and Daniela Saraí Rodríguez-Rangel for reviewing the language in the manuscript.
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