Mitochondrial emitted electromagnetic signals mediate retrograde signaling
Introduction
Human cells contain several organelles specialized to perform specific tasks while their position within the cell as well as their functions are tightly coordinated by a yet unknown mechanism. Moreover, some cellular organelles form pairs which are structurally and/or functionally interconnected. For instance, mitochondria and endoplasmic reticulum are both structurally and functionally interconnected [1], [2], while mitochondria and nucleus as well as endoplasmic reticulum (ER) and nucleus are only functionally connected [3], [4].
The ability of mitochondria to regulate nuclear gene expression, known as mitochondrial retrograde signaling was first discovered in yeast and then in all living organisms from plants to mammals [5], [6]. In normal cell functioning conditions, the mitochondria-nucleus bidirectional communication coordinates the two genomes and ensures mitochondrial biogenesis. The mitochondrial genome produces only a small percentage of the proteins required for the mitochondrial biogenesis while the vast majority of mitochondrial proteins (more than 1.000) are nuclear-encoded. For example, cytochrome c oxidase contains 13 subunits, 3 of which are mitDNA-encoded and the remaining 10 are nuclear DNA-encoded. This evidence points towards the existence of a highly coordinated network connecting the two different genomes [7], [8].
Additionally, there is evidence that mitochondria and nucleus are also tightly coordinated under cell stress conditions [6], [8], [9], [10], [11]. Mitochondrial dysfunction, regardless of the cause, is accompanied by: MMP value alterations (hyper- or depolarization), loss of MMP fluctuations, diminished ATP production and mitochondrial oxygen consumption (mitochondrial respiration) as well as ROS overproduction. In these cases, due to the fact that mitochondria cannot provide the required amounts of ATP, cells are forced to change their bioenergetic profile in order to survive [10], [12]. The phenomenon was first observed in cancer cells back in 1924 by Otto Warburg, who suggested that mitochondrial bioenergetic deregulation is the hallmark for cancer cells metabolism which shifts from oxidative to aerobic glycolytic ATP production [13].
Although this original observation is correct, it does not exhaust the ways cancer cells develop in order to produce or even acquire the required amounts of ATP [10]. For example, certain cells of solid tumors can produce ATP under glucose deprivation conditions [14]. Additionally, certain cancer cell lines can efficiently produce higher than normal amounts of ATP (possibly by developing alternative pathways) although mitochondrial performance has been compromised [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27].
It is well-known that in the case of prolonged mitochondrial dysfunction the nuclear transcriptional activity is drastically changed as cells acquire an alternative metabolic profile and an oncogenic phenotype [12]. The resulting changes affect not only nuclear-encoded mitochondrial proteins but also proteins of almost all cellular systems. Thus, mitochondrial retrograde signaling controls nuclear activity and in that way every aspect of the cell function including cell fate [14], [28].
The most characteristic of the resulting changes observed in mitochondrial dysfunction are: (i) the reduction of ATP which is accompanied by an analogous increase in ROS [29], (ii) altered performance of nuclear transcriptional factors and several coactivators [5], [7], [30], [31], (iii) reprogramming of nuclear gene transcriptional activity [10], (iv) changes in the function of a huge spectrum of kinases [7], (v) abnormalities in protein phosphorylation/dephosphorylation [32], (vi) induction of mitochondrial uncoupling protein response (UPR) [14], (vii) disturbance of cytosolic nucleotide metabolism [33], (viii) reversal of the function of p53 and AMPK tumor suppressors which become tumor promoters [34], [35], (ix) deregulation of protein post-translational modification [36].
In contrast, normal mitochondrial activity has beneficial effects on both normal and cancer cells. It has been reported that restoration of mitochondrial performance reverses cancerous morphogenesis [37] and the cardiac cell damage caused in case of ischemia regardless of the severity of the attack [38]. Furthermore, signaling from normal mitochondria to nucleus suppresses several oncogenic pathways [39].
Although retrograde signaling has been extensively investigated, neither the mitochondrial factor nor the underlying mechanism has been identified as yet [8], [36], [40]. Several mediators of retrograde signaling such as ATP, ROS, calcium signaling, kinases, groups of transcriptional factors etc. have been proposed. Although alterations of these factors can affect the nuclear function, they can all be excluded because of lack of specificity as changes in their levels or function affect the function of almost all cellular systems. For example, changes in ATP and ROS levels that have been implicated in nucleus reprogramming are secondary events due to mitochondrial dysfunction which, in turn, is driven by abnormal MMP values [29], [41]. Also, it is well-known that deregulation of ATP and ROS production negatively affects the function of all cellular factors (kinases, transcriptional factors etc.). That is, the changes in the aforementioned factors which have been implicated as mediators in retrograde signaling are orchestrated by the MMP value.
Additionally, it has been reported that MMP value deregulation affects differently nuclear gene expression as some groups of them are up-regulated while others are down-regulated [5]. These original observations have been ignored as the endogenously produced electric currents, potentials and fields are considered as epiphenomena (or wasteful byproducts) rather than active biological factors [42], [43]. The evidence presented below clearly shows that MMP and mitochondrial emitted electromagnetic fields (EFs) are indeed two powerful biological factors which regulate several important biological activities including the nucleus transcriptional activity.
Section snippets
Hypothesis on retrograde signaling regulation
This paper proposes that retrograde signaling is accomplished by the interaction between mitochondrial EF and nuclear receptors. The first acts as an electromagnetic signal (signaling factor) and the second as ligand-independent activated electromagnetic receptors. The interaction between EF and nuclear receptors is absolutely specific as each nuclear receptor has its own absorption band and it can be activated only by electromagnetic signals with specific frequencies. In normal conditions, EF
Mitochondrial functions
Mature cells, with the exception of erythrocytes which do not possess mitochondria, contain from 300 to 3000 mitochondria either isolated or in sheets while activated oocytes contain hundreds of thousands of mitochondria [44], [45]. In normal conditions, mitochondria produce more than 90% of ATP and small quantities of ROS as a byproduct. In case of mitochondrial dysfunction, ATP production collapses and mitochondria produce large quantities of ROS. Recent evidence shows that mitochondria can
Mitochondrial membrane potential functional properties
Nowadays, MMP can be accurately measured with several fluorescent dyes (voltmeters), both in isolated mitochondria and intact cells [19], [20]. The results show that in physiological conditions the MMP value fluctuates (MMP is charged and discharged) between −108 and −159 mV, with a mean value of about −139 mV (inside negative) [21], [22], [23]. This mean value is the optimal for maximum ATP production for all species regardless of their structural differences [21], [24], [25]. The higher MMP
Mitochondrial emitted electromagnetic fields
Considering the 5 nm width of mitochondrial membrane, the MMP value of about −140 mV induces an electromagnetic field (EF) in the order of 3 × 107 V/m which is stronger than the electric field produced by the lightning bolt [20], [74]. That is, the mitochondrial electrostatic potential (MMP) is accompanied by a strong electromagnetic field. The electrostatic potential and the electromagnetic field are the two sides of the same entity. Depending on the detection technique, the mitochondrial emitted
The nuclear receptors (NRs)
For many years, it has been known that the nuclear membrane contains dozens of NRs [112]. More recent evidence shows that there exist several families of NRs and each family consists of many members and theirs isoforms. For example, there have been found three retinoid orphan receptors (RORs), alpha, beta and gamma (RORα, β, and γ). Each one of ROR genes can generate more than one isoforms (e.g. RORγ1 and γ2) [113]. More than half of NRs are called “orphan receptors” as they can be activated in
Nuclear receptor activation by electromagnetic signals (light)
There is abundant evidence that NRs from all organisms are activated by light (from far-red to UV). Thus, light regulates NR activity, nuclear gene expression and protein production [123], [124]. Light, visible and invisible, is part of a wider spectrum of electromagnetic waves. The energy carried by light is proportional to its frequency (E = h.v) where h is the Plank constant and v is the wave frequency. A high frequency electromagnetic wave has higher energy than a low frequency one. UV is
Conclusion
The presented evidence strongly supports a new hypothesis regarding the mechanism of retrograde signaling. According to this hypothesis, mitochondrial emitted electromagnetic signals (EF) can activate NRs and regulate nuclear gene expression. In normal conditions, the low EF frequencies activate the group of NRs responsible for normal cell phenotype and bioenergetic profile. In cancer cells, MMP hyperpolarization which is accompanied by permanently high EF frequencies can activate the NRs group
Conflict of interest
The authors declare that there is no conflict of interest for the present work.
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