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Pineal gland is a unique organ which is localized in the geometric center of the human brain. Its size is individually variable and the average weight of pineal gland in human is around 150 mg , the size of a soybean. Pineal glands are present in all vertebrates . Pineal-like organs are also found in non-vertebrate organisms such as insects [3,4,5]. It appears that the sizes of pineal glands in vertebrates are somehow associated with survival in their particular environments and their geographical locations. The more harsh (colder) their habitant, the larger their pineal glands are. A general rule is that the pineal gland increases in size in vertebrates from south to north or from the equator to the poles . It is unknown whether if the same species moved to a different environment this would cause a change in the size of their pineal gland.
It was reported that several physiological or pathological conditions indeed alter the morphology of the pineal glands. For example, the pineal gland of obese individuals is usually significantly smaller than that in a lean subject . The pineal volume is also significantly reduced in patients with primary insomnia compared to healthy controls and further studies are needed to clarify whether low pineal volume is the basis or a consequence of a functional sleep disorder . These observations indicate that the phenotype of the pineal gland may be changeable by health status or by environmental factors, even in humans. The largest pineal gland was recorded in new born South Pole seals; it occupies one third of their entire brain [9,10]. The pineal size decreases as they grow. Even in the adult seal, however, the pineal gland is considerably large and its weight can reach up to approximately 4000 mg, 27 times larger than that of a human. This huge pineal gland is attributed to the harsh survival environments these animals experience .
The human pineal gland has been recognized for more than 2000 years. The father of anatomy, the Greek anatomist, Herophilus (325–280 BC), described the pineal gland as a valve of animal memory. René Descartes (1596–1650), a French philosopher, mathematician, and scientist, regarded the pineal gland as the principal seat of the soul and the place in which all thoughts are formed. A real biological function of pineal gland was not uncovered until 1958 , that is, this gland is a secretory organ which mainly produces and releases a chemical, called melatonin, into the blood circulation and into the cerebrospinal fluid (CSF). In addition, it also produces some peptides [13,14] and other methylated molecules, for example, N,N-dimethyltryptamine (DMT or N,N-DMT) [15,16], a potent psychedelic. This chemical was suggested to be exclusively generated by the pineal gland at birth, during dreaming, and/or near death to produce “out of body” experiences . However, the exact biological consequences (if any) of these substances remain to be clarified. Recently, it was reported that pineal gland is an important organ to synthesize neurosteroids from cholesterol. These neurosteroids include testosterone (T), 5α- and 5β-dihydrotestosterone (5α- and 5β-DHT), 7α-hydroxypregnenolone (7α-OH PREG) and estradiol-17β (E2). The machinery for synthesis of these steroids has been identified in the gland. 7α-OH PREG is the major neurosteroid synthesized by the pineal gland. Its synthesis and release from gland exhibits a circadian rhythm and it is regulates the locomote activities of some vertebrates, especially in birds . These observations opened a new avenue for functional research on pineal gland; the observations require further confirmation.
The most widely accepted concept is that melatonin is the recognized major product of the pineal gland. Melatonin is the derivative of tryptophan. It was first isolated from the pineal gland of the cow and it was initially classified as a neuroendocrine-hormone . Subsequently, it was discovered that retina [20,21] and Harderian gland [20,22,23,24] also produced melatonin. Recently, it has been found that almost all organs, tissues and cells tested have the ability to synthesize melatonin using the same pathway and enzymes the pineal uses [25,26]. These include, but not limited to, skin , lens , ciliary body [29,30], gut [31,32], testis , ovary [34,35], uterus , bone marrow [37,38], placenta [39,40], oocytes , red blood cells , plantlets , lymphocytes , astrocytes, glia cells , mast cells  and neurons . Not only melatonin but also the melatonin biosynthetic machinery including mRNA and proteins of arylalkylamine N-acetyltransferase (AANAT) and/or N-acetyl-serotonin methyltransferase (ASMT) [formerly hydroxyindoleO-methyltransferase (HIOMT)] have been identified in these organs, tissues and cells. It was calculated that the amounts of extrapineal derived melatonin is much greater than that produced by the pineal . However, the extra pineal-derived melatonin cannot replace/compensate for the role played by the pineal-derived melatonin in terms of circadian rhythm regulation. As we know pineal melatonin exhibits a circadian rhythm in circulation and in the CSF with a secretory peak at night and low level during the day ; thus, the primary function of the pineal-derived melatonin is as a chemical signal of darkness for vertebrates . This melatonin signal helps the animals to cope with the light/dark circadian changes to synchronize their daily physiological activities (feeding, metabolism, reproduction, sleep, etc.).
For the photoperiod sensitive reproductive animals, the melatonin signal regulates their reproductive activities to guide them to give birth during the right seasons . Interestingly, even low ranking species that lack a pineal gland, for example, marine zooplankton, also exhibit a melatonin circadian rhythm which is responsible for their daily physiological activities . While, the extrapineal melatonin in vertebrates does not contribute to the melatonin circadian rhythm and it does not serve as the chemical signal of darkness since pinealectomy in animals distinguishes this rhythm [52,53,54]. This was further confirmed by the recent discovery that the expressions of AANAT and ASMT are present in mitochondria of both pinealocytes and neuron cells and their mitochondria synthesized melatonin. However, the expressions of AANAT and ASMT exhibit a circadian rhythm that matched the fluctuation in melatonin levels only in the mitochondria of pineal gland while this rhythm was absent in the mitochondria of neuronal cells . Thus, the primary function of extrapineal melatonin (except for the retina; retinas not only possess an internal melatonin rhythm [56,57]; retinal melatonin might participate in melatonin circadian rhythm of the general circulation in some species [58,59,60]) is to serve as an antioxidant, autocoid, paracoid and tissue factor locally [49,61].
In addition to synthesizing the “signaling-melatonin” which differs from extrapineal melatonin, the pineal gland also participates in the CSF production and recycling. The blood filtration rate of this gland is comparable to the kidney ; this is, far more than its metabolic requirement. It was hypothesized that pineal gland may function like the kidney as a blood filter to generate CSF; this is similar to the function of choroid plexus to recycle the CSF . Pineal gland and choroid plexus share a similar vasculature structure with the abundance of the vasculature spaces and fenestrated capillaries. A direct morphological connection between pineal gland and choroid plexus has been reported in birds . The functional and vascular structural similarities may explain the high calcification rates of both structures [65,66].
The calcium deposits in the pineal gland were recognized several decades ago in vertebrates [67,68]. Some researchers believe that pineal calcification was associated with certain endocrine diseases such as schizophrenia, and mammary carcinoma [69,70,71,72,73,74,75]. Others feel that it is a natural process and has no consequences for human physiopathology since this process occurs early in childhood  and it also may not impact the melatonin synthetic ability of the gland in some animals [77,78]. Recently, additional studies have shown that pineal calcification indeed jeopardizes the melatonin production in humans and it seems to have a direct influence on neurodegenerative diseases and aging [79,80,81]. This review summarizes the current developments in the field and also provides opinions and comments on pineal physiology and pineal gland calcification (PGC).
2. Pineal Gland and the Melatonin Circadian Rhythm
The pineal gland is situated in the geometric center of the human brain and it is directly connected to the third ventricle; it is classified as a circumventricular organ (CVO) and participates in the biological rhythm regulation in vertebrates. Herein, we refer to the structures which regulate biorhythms as the suprachiasmatic nucleus (SCN)-melatonin loop. This loop includes melanopsin-containing retinal ganglion cells (MRGC), retino-hypothalamic tract (RHT), SCN, paraventricular nucleus (PVN), Intermediolateral cell column, sympathetic cervical ganglia (SCG), the pineal gland, melatonin rhythm which feedback impacts the SCN (Figure 1).
Any defect of the loop results in a diminished melatonin circadian rhythm and the disturbance of chronobiology. For example, SCN or PVN lesions [82,83,84], blockade of the cervical ganglia [85,86] or pinealectomy [52,53] is always accompanied by the loss of the melatonin rhythm in vertebrates. This loop is important to regulate the biological rhythms of vertebrates. SCN is believed to be the master clock or the pacemaker . This pacemaker has its internal circadian timer which is longer than 24 h. It is synchronized to 24 h circadian rhythm by the environmental photoperiod clues. However, melatonin is a major chemical message to synchronize its activity of SCN .
Melatonin membrane receptors have been identified in the SCN of vertebrates [56,89] and the signal transduction pathways seemed to be involved in both MT1 and MT2 to induce an increase in the expression of two clock genes, Period 1 (Per1) and Period 2 (Per2) [89,90,91]. Without the feedback information of melatonin, SCN would not properly interpret the natural photoperiodic changes  and would exhibit a free running internal rhythm in which the cycle is longer than 24 h. In this situation the SCN would also instruct the pineal gland to exhibit an unusual melatonin circadian rhythm which is also longer than 24 h. This phenomenon is apparent in completely blind animals and humans whose eyes, specifically the MRGC, do not appropriately receive environmental photoperiodic information [93,94,95]. Importantly, melatonin administration to blind subjects partially re-entrains their biological rhythms close to normal [94,96,97].
Pineal gland is mainly comprised of pinealocytes, microglia and astrocytes. The lineage of pinealocytes is elusive. Current information suggests that pinealocytes are differentiated from Pax6-expresssing neuroepithelial cells . They are specialized to synthesize and release melatonin (and possible some other substances). This explains why pinealocytes with two special characteristics regarding their mitochondria. First, the pinealocytes contain many more mitochondria than those of neuronal cells. Second, the morphologies of these mitochondria exhibit obvious dynamic alterations related to their fission, fusion and mitophagy activities during a 24 h period . Because of the high density of mitochondria, we speculated the mitochondria are the major sites for melatonin synthesis . Subsequent studies have proven this speculation. Melatonin synthesis was identified in the mitochondria of both animal and plant cells [101,102]. Recently, this was further confirmed by Suofa et al. . They observed that the mitochondria are the exclusive sites of melatonin production in pinelocytes and in neuronal cells. The exact subsite of melatonin synthesis occurred in the matrix of mitochondria. Thus, the numerous mitochondria in pinealocytes relate to their melatonin synthetic function. This does not naturally exclude the extra-mitochondrial melatonin production. In cytosol, melatonin can also be synthesized. For example, red blood cells and platelets which are without mitochondria still produced melatonin [42,43]. Due to the substrate, particularly acetyl coenzyme A availability, melatonin synthesis in the extra-mitochondrial sites would not be as efficient as in the mitochondria since acetyl coenzyme A is concentrated in the mitochondria .
As to the mitochondrial dynamic alterations, generally, at darkness when melatonin is at its synthetic peak, more mitochondrial fusion was observed and, during the day, more fission was obvious. It was speculated that the mitochondrial dynamic changes were associated with their function, i.e., to produce melatonin . However, current studies have reported that melatonin per se can regulate mitochondrial morphology [104,105]. Melatonin upregulates the levels of mitochondrial fusion proteins mitofusin 1 (Mfn1) and Opa1 to promote mitochondrial fusion [106,107] and inhibits the nuclear translocation of dynamin-related protein 1 (DrP1). The nuclear translocation of DrP1 increases mitochondrial fission and the inhibition of DrP1 nuclear translocation by melatonin results in suppression of mitochondrial fission [108,109,110,111,112]. Thus, the net result of melatonin is to promote the mitochondrial fusion and to reduce mitochondrial fission.
The effects of melatonin on mitophagy are still elusive. Some reports document that melatonin inhibits mitophagy and others show that melatonin promotes this process depending on the experimental conditions and cell type [109,113,114,115,116,117,118,119,120,121]. Currently it is not possible to determine whether the mitochondrial dynamic changes in pinealocytes relate to their functional activity which may be controlled by the clock genes, such as perd1, 2 or a result of their melatonin production rhythm. Thus, do the changes in melatonin levels generated by pinealocytes result in the mitochondrial dynamic changes.
In addition to the pinealocytes, the astrocytes and the microglia in the pineal gland also have the capacity to synthesize melatonin with great efficiency. The melatonin synthetic machinery including AANAT/SNAT and HIOMT/ASMT has been identified and melatonin production has been detected in these cells [45,122]. Markus et al. [123