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Rebecca Heidker

Intersections of Pathways Involving Biotin and Iron Relative to Therapeutic Mechanisms for Progressive Multiple Sclerosis

Abstract: While there are a variety of therapies for relapsing remitting multiple sclerosis (MS), there is a lack of treatments for progressive MS. An early study indicated that high dose biotin therapy has beneficial effects in approximately 12-15% of patients with progressive MS. The mechanisms behind the putative improvements seen with biotin therapy are not well understood, but have been postulated to include: 1) improving mitochondrial function which is impaired in MS, 2) increasing synthesis of lipids and cholesterol to facilitate remyelination, and 3) affecting gene expression. We suggest one reason that a greater percentage of patients with MS didn't respond to biotin therapy is the inaccessibility or lack of other nutrients, such as iron. In addition to biotin, iron (or heme) is necessary for energy production, biosynthesis of cholesterol and lipids, and for some protective mechanisms. Both biotin and iron are required for myelination during development, and by inference, remyelination. However, iron can also play a role in the pathology of MS. Increased deposition of iron can occur in some CNS structures possibly promoting oxidative damage while low iron levels can occur in other areas. Thus, the potential, detrimental effects of iron need to be considered together with the need for iron to support metabolic demands associated with repair and/or protective processes. We propose the optimal utilization of iron may be necessary to maximize the beneficial effects of biotin. This review will examine the interactions between biotin and iron in pathways that may have therapeutic or pathogenic implications for MS.



Introduction

The pathogenesis of multiple sclerosis (MS) involves demyelination, axonal degeneration, and neuronal loss, which results in a range of deficits including sensory, motor, and/or cognitive impairments. Although there is an array of disease modifying therapies (DMTs) for relapsing remitting MS (RRMS) (Fogarty et al., 2016), there is a need for DMTs that alleviate the progressive forms of disease. Early clinical trials suggest that high dose biotin therapy (HDBT) may have some value for primary (PPMS) and secondary (SPMS) progressive MS (Sedel et al., 2015; Tourbah et al., 2016). If substantiated, this could represent an important step forward in the effort to combat progressive MS (Chataway, 2016). While we await further studies, it is relevant to examine how biotin is utilized for oligodendrocyte biology, by potential CNS repair mechanisms, and for other therapeutic actions. In addition, it is pertinent to recognize that the mechanisms involved in HDBT rely on other biomolecules for their effectiveness.

Biotin is a required cofactor for five enzymes necessary for glucose, fatty acid, and/or amino acid metabolism: pyruvate carboxylase (PC), acetyl-CoA carboxylase (ACC, isoforms 1 and 2), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). Interestingly, iron is also required for putative therapeutic mechanisms involving HDBT. Iron, in conjunction with PC and MCC, is involved with heme synthesis (Voet and Voet, 2011). Heme and iron-sulfur clusters are cofactors for multiple enzymes involved in lipid and cholesterol synthesis (Connor and Menzies, 1996; Vergeres and Waskell, 1995), as well as being required for ATP synthesis via oxidative metabolism (Voet and Voet, 2011).

Illness can increase the demand for many nutrients beyond recommended intake levels. In MS, suboptimal availability of the nutrients biotin and/or iron could impede mitochondrial respiration, remyelination, and cellular defense mechanisms. Thus, supplementation of these nutrients could have potential therapeutic relevance. While high levels of biotin are generally thought to be safe (Peyro Saint Paul et al., 2016), iron may have a more complex role in MS. Beginning early in the disease, iron can accumulate in CNS structures, e.g., caudate, globus pallidus, and putamen (Weigel et al., 2014). Excess or mismanaged iron has the capacity to promote oxidative tissue damage (Williams et al., 2012; Weigel et al., 2014); however, other areas may have too little iron or undergo a virtual anemic cellular state (where iron is unavailable for use despite adequate or high tissue levels) that may contribute to pathology by limiting metabolism and impeding repair and defense mechanisms (Stephenson et al., 2014; Drakesmith and Prentice, 2008). Since various putative therapeutic pathways involving biotin also rely on iron, an optimal management of iron would be necessary for a more favorable outcome. Here we examine the interrelationships between biotin and iron in the context of MS.

Preliminary Studies Suggest that High-dose Biotin May Have Therapeutic Value for Progressive MS

After four patients with a leukodystrophy showed improvements following HDBT (Sedel et al., 2011), one patient was determined to have SPMS (Sedel et al., 2015). This led to an unblinded trial of HDBT in 23 patients with progressive MS (Sedel et al., 2015). Encouraging results in this open label study (Sedel et al., 2015) prompted a larger study. Biotin (100 mg; n = 103) or placebo (n = 51) was given three times daily to patients with PPMS or SPMS for 12 months in a double blind study, and then all patients (n = 91 and n = 42 from the original biotin and placebo groups, respectively) received biotin for an additional 12 months in an open label study (Tourbah et al., 2016). At 9 months, the double blind portion of the study found that biotin reversed progression [improved time on a 25-foot walk (TW25) and/or improved expanded disability status scale (EDSS) scores] in 12.6% of the treated group compared to 0% in placebo group. The open-label portion of the study, i.e., at the 24-month time point, showed improvement in 15.5% and 11.9% of the patients in the original biotin and placebo arms, respectively. Although these are encouraging results, only two subjects in the treated groups had improvements on both the TW25 and EDSS, with three patients having gains only in TW25 and eight patients with gains only in EDSS (Tourbah et al., 2016; Chataway, 2016). Furthermore, the baseline of the EDSS of subjects and proportions SPMS-to-PPMS patients were not evenly balanced between biotin and placebo groups, and although the MRI analysis was incomplete, 23% of the patients on biotin and 13% on placebo showed new T2 lesions at 12 months (Tourbah et al., 2016; Chataway, 2016). Thus, additional analyses (e.g., MRI measurements of brain atrophy) and independent confirmation of these findings are necessary before HDBT can be considered successful (Chataway, 2016).

Sub-optimal biotin levels may contribute to MS pathology. One study observed that MS patients have lower CSF levels of biotin compared to control subjects (Anagnostouli et al., 1999). Given the improvements seen with HDBT, Sedel et al. (2016) provided two primary hypotheses regarding potential therapeutic mechanisms: enhancing remyelination and promoting energy production. In theory, HDBT would act to enhance remyelination by facilitating ACC activity, which in turn would facilitate fatty acid biosynthesis for myelin production (Sedel et al., 2016). With respect to energy production, Sedel et al. (2016) proposed that biotin facilitates the activities of PC, MCC, and PCC, all of which generate intermediates for the citric acid (TCA) cycle. Improved function of the TCA cycle may act to protect axons/neurons that have undergone demyelination and/or developed virtual hypoxia. We provide additional information about how biotin could support energy and myelin production, and have additional mechanisms of action for progressive MS.

An Interrelationship Between Biotin and Iron in Heme Synthesis

Heme is vital for mitochondrial metabolism (Voet and Voet, 2011), steroid and lipid biosynthesis, the antioxidant catalase, etc. As heme is not recycled, it must be synthesized de novo, requiring both biotin and iron for the process. The biotin dependent enzymes PC and MCC are required for production of succinyl-CoA and glycine, which are used to generate protoporphyrin IX (Voet and Voet, 2011). Ionic iron becomes the central moiety of this molecule, thus forming heme (Voet and Voet, 2011). Deficiencies in PCC enzyme activity in peripheral blood lymphocytes are thought to be an early indicator of marginal biotin deficiency, and severe deficiencies can lead to anemia (Stratton et al., 2006; Shchelochkov et al., 2016). Therefore, sub-optimal levels of iron and/or biotin can potentially decrease heme production (Atamna et al., 2007; Voet and Voet, 2011); however, this remains to be explored in the CNS.

Insufficient heme is linked to loss of mitochondrial complex IV, oxidative stress, and apoptosis (Atamna, 2004). Biotin deficiency in primary human lung fibroblast cells (IMR90) has been shown to decrease heme synthesis with a concomitant decrease in iron uptake (Atamna et al., 2007). Biotin deficiency in these cells also resulted in a higher production of oxidants, greater oxidative damage, and earlier senescence (Atamna et al., 2007). This lack of heme is postulated to be the cause of decreased activity in complex IV (Atamna et al., 2007), and decreases in this complex occur in demyelinated axons and in some MS lesions (e.g., Pattern III) (Mahad et al., 2009; 2008).

A deficiency of biotin could inhibit proper mitochondrial functioning, making cells more vulnerable to energy deficits and virtual hypoxia. Both membrane repolarization in neurons and myelin production by oligodendrocytes utilize high levels of ATP (Harris and Attwell, 2012). Furthermore, mitochondrial content and complex IV activity are increased in remyelinating axons (Zambonin et al., 2011) suggesting a higher demand for biotin and heme.

Oligodendrocyte Lineage Cells Are Sensitive to Energy Deprivation

Oligodendrocytes are very metabolically active (Amaral et al., 2016), utilizing high levels of glucose and lactate (Funfschilling et al., 2012; Sanchez-Abarca et al., 2001). Acetyl-CoA generated from these substrates is used to produce lipids and cholesterol, which are essential for the synthesis and maintenance of myelin (Clarke and Sokoloff, 1994; Harris and Attwell, 2012). Mature oligodendrocytes can reduce glycolytic metabolism, decreasing myelin production in response to stressors, i.e., hypoxia or hypoglycemia, to promote cell survival (Rone et al., 2016; Yan and Rivkees, 2006). Oligodendrocyte progenitor cells are unable to decrease their metabolic rate, and hypoxic stress results in high levels of cell death, decreasing the maturation of new oligodendrocytes that can participate in remyelination (Rone et al., 2016).

Biotin plays a critical role in cellular energy production. The mitochondrial biotin dependent enzymes PCC, MCC, and PC are utilized in creation of the TCA cycle intermediates succinyl-CoA, acetyl-CoA, and oxaloacetate; while the cytoplasmic ACC1 plays a key role in fatty acid synthesis (Voet and Voet, 2011). Succinyl-CoA and acetyl-CoA are also crucial for the production of heme and lipids/cholesterol, respectively (Voet and Voet, 2011), while oxaloacetate is essential for anaplerotic replenishment of the TCA cycle in oligodendrocytes (Amaral et al., 2016). The TCA cycle feeds the electron transport chain where iron in the form of iron-sulfur clusters and in cytochromes is necessary for generation of additional ATP (Voet and Voet, 2011). Therefore, depletions of iron and/or biotin could limit energy production by oligodendrocytes, and in doing so making them less capable of forming or maintaining myelin; potentially even affecting oligodendrocyte survival during MS inflammation.

Neuronal Virtual Hypoxia

Biotin and iron are important for the support of oxidative metabolism in neurons. Approximately 20% of the body’s resting mitochondrial oxygen consumption occurs in the brain and generates ATP, which is vital to maintaining neuronal membrane potentials (Clarke and Sokoloff, 1994). The imbalance between energy supply and demand, known as virtual hypoxia, has been proposed as a pathogenic mechanism in MS. For instance, the loss of myelin along the axon changes Na+ channel distribution leading to increased energy demand within the axon (Trapp and Stys, 2009; Witte et al., 2014). Demyelination necessitates restoring membrane potential along the length of the axon, rather than only at the nodes of Ranvier, where Na+ channels locate normally (Craner et al., 2004; Su et al., 2009). Mitochondria ultimately fail to sufficiently meet the increased demand for energy resulting in diminished Na+/K+ ATPase activity and loss of ionic gradient control (Su et al., 2009). Prolonged depolarization and increased intracellular Na+ concentration due to insufficient energy creates potentially damaging Ca2+ imbalances within the cell through Na+/Ca2+ exchanger dysfunction (Stys et al., 1992; Dutta et al., 2006).

In certain neuronal populations, the cell body supporting the demyelinated axon attempts to compensate with redistribution and increased speed of motile mitochondria along the axon (Mahad et al., 2009; Kiryu-Seo et al., 2010). Remyelinated axons in MS demonstrate an increased number of mitochondria compared to myelinated axons, although restoration of the energy balance seems to be limited (Zambonin et al., 2011; Campbell et al., 2014). Mitochondria utilize axonal transport mechanisms to reach sites of energy need; however, if energy supply is already attenuated, this process may be inadequate if axonal transport is inefficient due to lack of ATP (Su et al., 2009). Disruption of metabolism in support of oligodendrocytes may also exacerbate the effects of virtual hypoxia, as oligodendrocytes support neurons by providing pyruvate and lactate via the monocarboxylate transporters 1 and 2 (Funfschilling et al., 2012). If the neuronal soma cannot maintain a healthy mitochondrial level, axonal damage may occur (Witte et al., 2014). Activation of the permeability transition pore in failing mitochondria results in release of cytochrome C, potentially triggering apoptotic pathways (Su et al., 2009). Achieving optimal levels of biotin and iron could help meet energy demands, thereby ameliorating virtual hypoxia.

Biotin and Iron Are Required for Growth of Oligodendrocytes and Formation of Myelin

In humans, myelin is composed of approximately 70% lipids, with nearly 28% of this amount being cholesterol (Morell et al., 1994). The other primary lipid components of myelin include phospholipids and galactolipids, e.g., galactosylceramide and sulfatide (Morell et al., 1994). The majority of cholesterol, as well as the saturated and monounsaturated fats used in the brain, is synthesized endogenously within the CNS (Jurevics and Morell, 1995; Edmond et al., 1998). Biotin is a required cofactor for ACC1, which initiates lipid biosynthesis (Voet and Voet, 2011). ACC has a high activity and an enriched expression within oligodendrocytes during myelination (Tansey et al., 1988; Tansey and Cammer, 1988). Biotin is also enriched within oligodendrocytes as shown in rodent CNS tissue (LeVine and Macklin, 1988). In vitro studies observed that biotin is required for the growth and survival of oligodendrocytes (Bottenstein, 1986), with deficiencies resulting in the attenuation of myelin/white matter formation. Biotin responsive multiple carboxylase deficiency (MCD) may be caused by decreased enzymatic activity of either holocarboxylase synthetase (HCS; adding biotin to carboxylases) or biotinidase (releasing/recycling biotin) (Wolf, 2000; Pacheco-Alvarez et al., 2002). Demyelination, axonal loss, and behavioral changes have been observed in mice deficient for biotinidase and these alterations are lessened with biotin administration (Pindolia et al., 2012). In humans, biotinidase deficiency can result in a reduction of white matter, e.g., delayed myelination, cerebral atrophy, vision and hearing difficulties, seizures, hypotonia, and slow motor development (van der Knaap and Valk, 2005). One report describes neurological features resembling MS (Tokatlι et al., 1997). Early biotin supplementation (6-17 months of age) can reverse these symptoms (Bousounis et al., 1993); however, if left until later (i.e., 7 years of age), supplementation appears to reverse ataxia, but not sensorineural challenges (Thuy et al., 1986). In addition to biotinidase or HCS deficiencies, mutations in individual carboxylases that utilize biotin, such as PC, result in decreased white matter development and neurological dysfunction (Marin-Valencia et al., 2010).

Similarly, iron deficiencies during prenatal and early postnatal development result in decreased myelination due to inhibited syntheses of lipids, cholesterol, and myelin associated proteins in both humans and animals (Roncagliolo et al., 1998; Algarin et al., 2003; Yu et al., 1986; Ortiz et al., 2004). These changes have been attenuated with iron supplementation (Roncagliolo et al., 1998; Algarin et al., 2003). Iron is normally enriched within oligodendrocytes in the CNS tissue (LeVine, 1991; LeVine and Macklin, 1990), and in vitro studies indicate that iron (i.e., via transferrin or ferritin) is required by oligodendrocytes for growth and survival (Bottenstein, 1986; Todorich et al., 2011). Iron is required to support the metabolically expensive processes of cholesterol and lipid synthesis, with both the temporal uptake and spatial distribution of iron coinciding with peak myelination (Taylor and Morgan, 1990; Connor and Menzies, 1996). Cytochrome b5, which contains heme, is also necessary for enzymes involved in lipid and cholesterol synthesis (reviewed in Vergeres and Waskell, 1995). Iron is also necessary for many enzymes utilized in DNA transcription and translation, e.g., ribonucleotide reductase, DNA primase, and the ATPase ABCE1 (Drakesmith and Prentice, 2008).

Ongoing inflammation can result in anemia of inflammation, which is a state of low serum iron despite sufficient iron stores (Nemeth and Ganz, 2014). Interestingly, chronic progressive MS patients have lower levels of iron in normal appearing white matter (which has a low degree of inflammation) as compared to subjects with a short duration of disease and normal subjects, with the changes in iron levels being correlated with duration of disease (Hametner et al., 2013). The prevalence of anemia may be greater in MS patients compared to control subjects (Koudriavtseva et al., 2015); however, MS patients can have elevated deposition of iron in numerous CNS structures (e.g., caudate and thalamus) (Williams et al., 2012; Weigel et al., 2014). It is unknown whether this excess iron is accessible for cellular functions to meet cellular demands for remyelination and high energy metabolism or if it is unavailable, e.g., sequestered in macrophages or a consequence of neurodegeneration.

Excess Iron May Promote Pathology

Although iron is required for mitochondrial function and remyelination, it might also contribute to pathogenesis. Abnormal iron deposition is seen in both gray and white matter structures of MS patients (Williams et al., 2012; Weigel et al., 2014). Some of this iron has been associated with oxidation products in MS and experimental autoimmune encephalomyelitis (EAE), and may contribute to mitochondrial dysfunction (Hametner et al., 2013; Williams et al., 2012; Weigel et al., 2014). Additionally, the damaged blood-brain barrier that occurs in MS and EAE may allow extravasation of red blood cells into the CNS, which leads to heme/iron catalyzing the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Weigel et al., 2014). These radicals cause chemical modifications of biomolecules in surrounding tissue, damaging functionality and leading to epitope spreading (Vanderlugt and Miller, 2002; Kanter et al., 2006). Mitochondrial injury/loss may also be exacerbated by ROS and RNS produced through activated microglia and macrophages (Fischer et al., 2012; Witte et al., 2010).

Additional Mechanisms of Action for Biotin

HDBT could have additional mechanisms of action, i.e., limiting the immune response, influencing signaling, and affecting gene expression (Rodriguez-Melendez and Zempleni, 2003). Biotin supplementation in healthy adult human subjects results in less proliferation of stimulated peripheral blood mononuclear cells and less IL-1β and IL-2 production by these cells (Zempleni et al., 2001), while biotin deficiency in Jurkat cells increases nuclear translocation of the inflammation promoting NF-κB (Rodriguez-Melendez et al., 2004). Recently, inflammatory responses in murine EAE have been inhibited through activation of AMPK/SIRT1 signaling by methylene blue (Wang et al., 2016). Biotin also activates AMPK in the liver (Aguilera-Méndez and Fernández-Mejía, 2012). Conversely, biotin deficiency in LPS stimulated human derived dendritic cells decreases activation of AMPK and increases expression of inflammatory cytokines (Agrawal et al., 2016). Additionally, biotinylation of histones in multiple human cell lines has been shown, with alterations during cell proliferation (Rodriguez-Melendez and Zempleni, 2003).

By supporting ATP production, biotin allows for the initial synthesis of NADPH, which is actively replenished by the pentose phosphate pathway (PPP) and is a necessary reducing agent for cholesterol and lipid synthesis (Voet and Voet, 2011). This pathway is highly active during peak myelination (Amaral et al., 2016). Additionally, the PPP generates glycolytic intermediates (Voet and Voet, 2011), as well as ribose-5-phosphate, which is necessary for nucleic acid synthesis (Stanton, 2012). NADPH is also critical for cellular systems including antioxidant and nitric oxide synthase enzymes (Stanton, 2012). Biotin supplementation of stimulated neutrophils modulates the pathway leading to NADPH oxidase activity and attenuates the production of superoxide anion radicals (Sekiguchi and Nagamine, 1994), suggesting a similar role in microglia and macrophages.

Conclusions

Preliminary studies indicate that HDBT may have value as a treatment for progressive MS. We raise the notion that to facilitate the putative therapeutic mechanisms, biotin likely works in concert with multiple other nutrients, and iron has a particularly integrated role with biotin. Both nutrients are closely involved in the production of heme and the support of metabolism, which can counter virtual hypoxia and promote remyelination.

Since the requirements for many nutrients are increased during illness, MS patients probably require higher than recommended levels of biotin. In addition, HDBT is likely activating protective and/or repair pathways beyond what sufficient biotin levels achieve. However, it is unclear if maintenance of a high dosage is needed over the patient’s lifetime. Fortunately, high levels of biotin, thus far, appear to be safe. Although HDBT appeared to help ~12-15% of progressive MS patients, the question could be asked why a greater percentage of patients didn’t respond. One possibility is that unresponsive patients had suboptimal levels of other nutrients such as iron limiting the response to biotin. Although iron can accumulate in some CNS structures (Williams et al., 2012; Weigel et al., 2014), it is depleted in others (Hametner et al., 2013), e.g., normal appearing white matter. It is possible that in areas with abnormal iron deposits the availability of iron for use by oligodendrocytes and neurons is limited. Determining whether virtual anemia occurs in neurons or oligodendrocytes in the context of virtual hypoxia would be relevant as these cells normally experience high energy demands that may be further increased during stress, demyelination, and/or remyelination.

HDBT has provided a glimpse into potential therapeutic mechanisms that may hold promise for progressive MS. Since some of these mechanisms point to improvements in metabolic processes, we suggest that other nutrients, particularly iron, are necessary for the optimal functioning of these pathways. In conclusion, HDBT may represent the start of a new focus on therapeutics that stimulate metabolism to enhance mitochondrial function and support remyelination in patients with progressive MS.

Disclosure

S.M.L. has received funding from ApoPharma, Inc.

Corresponding Author

Steven M. LeVine, Ph.D., Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 22(123):381-387, December 2016. Copyright © Discovery Medicine. All rights reserved.]

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