Mitochondrial Targeted Therapies: Where Do We Stand in Mental Disorders?

Accepted Manuscript Mitochondrial targeted therapies: where do we stand in mental disorders? Dorit Ben-Shachar, Hila M. Ene PII:

S0006-3223(17)31859-0

DOI:

10.1016/j.biopsych.2017.08.007

Reference:

BPS 13293

To appear in:

Biological Psychiatry

Received Date: 4 June 2017 Revised Date:

26 July 2017

Accepted Date: 6 August 2017

Please cite this article as: Ben-Shachar D. & Ene H.M., Mitochondrial targeted therapies: where do we stand in mental disorders?, Biological Psychiatry (2017), doi: 10.1016/j.biopsych.2017.08.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Mitochondrial targeted therapies: where do we stand in mental disorders?

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Dorit Ben-Shachar and Hila M. Ene

Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care

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Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for

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Research in Medical Sciences, Technion IIT, Haifa Israel.

Correspondence to: Prof. Dorit Ben-Shachar, Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus and B. Rappaport Faculty of Medicine, Technion ITT. POB 9649 Haifa, 31096, Israel. Tel: +972-4-8295224

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Fax: +972-4-8295220

email: [email protected]

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Abstract: 136 Text: 3934 Fig: 1 Tables: 0 Supplementary materials: 0

ACCEPTED MANUSCRIPT Abstract: The neurobiology of psychiatric disorders is still unclear, although changes in multiple neuronal systems, specifically the dopaminergic, glutamatergic and GABAergic systems as well as abnormalities in synaptic plasticity and neural connectivity, are currently suggested to underlie their pathophysiology. A growing body of evidence

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suggests multifaceted mitochondrial dysfunction in mental disorders, which is in line with their role in neuronal activity, growth, development and plasticity. In this review, we will describe the main endeavors towards development of treatments that will enhance mitochondrial function and their transition into clinical use, in congenital mitochondrial diseases and chronic disorders such as diabetes type I&II,

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cardiovascular disorders and cancer. In addition, we will discuss the relevance of mitochondrial targeted treatments to mental disorders and their potential to become a

Key words: Mitochondrial

targeted

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novel therapeutic strategy that will improve the efficiency of the current treatments.

treatments;

biogenesis,

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mitochondrial transplantation; psychiatric disorders

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bioenergetics,

antioxidants;

ACCEPTED MANUSCRIPT Introduction: Mitochondria are one of the hub spots of the cells, by the virtue of being the suppliers of its energy demands in the form of ATP, of various metabolites via the citric acid cycle (CAC) and of heme and steroids. ATP and the metabolites are the driving force and building blocks for a variety of macromolecules including proteins,

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lipids, carbohydrates and nucleotides. In addition, mitochondria have a key role in the quality control mechanisms of cells, by buffering intracellular Ca2+ concentrations, generating reactive oxygen species (ROS) and inducing apoptosis, all essential signaling for cell survival or death. The communication between mitochondria and the cell is bidirectional, not only because the majority of their proteins and essential

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factors for mtDNA replication are encoded by the nuclear DNA (nDNA) (1–3), but also since mitochondria respond to cellular state and energy demands transmitted by

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signaling molecules. Ca2+, protein kinases (4–7), and neurotransmitters, including glutamate, dopamine and serotonin (8–11) are such signaling molecules transferring information from the cytosol to the mitochondria. One cellular site in which this bidirectional intracellular signaling occurs is the endoplasmic reticulum (ER) mitochondria junctions, termed mitochondria-associated membranes (MAM), which were shown to play a key role in physiological and pathological processes (12). Given this intricate interaction between the cell and the mitochondria and their

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essential role in cellular survival and death, it is not surprising that mitochondrial dysfunction is observed in diverse genetic and chronic pathologies. Mitochondrial diseases, caused by mutation in either nDNA or mtDNA encoded genes, can affect various organs or tissues of the body including brain, heart, liver, kidney, lungs and

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muscles and are usually manifested from birth (13, 14). In chronic diseases, such as cancer, diabetes type II, neurological and psychiatric disorders and aging,

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multifaceted mitochondrial dysfunction has been observed including impairments in ROS production,

apoptosis,

respiratory chain activity,

Ca2+

buffering

and

mitochondrial network dynamics (15–22). Despite the last decades' intensive research on mitochondrial deficits and on

potential mitochondrial targeted treatments, no satisfactory treatment is currently available. Various approaches have been suggested and several were clinically applied, including pharmacological, nutritional, physical and more recently molecular and cellular approaches. These treatment approaches are mostly aimed at inactivation of ROS and apoptosis and balancing cellular bioenergetics homeostasis, for example by enhancing respiration, ATP production, and activation of the peroxisomal proliferator activator receptors / peroxisome proliferator-activated 3

ACCEPTED MANUSCRIPT receptor gamma coactivator 1-alpha (PPAR/PGC-1α) signaling. Clinically, short-term improvements have been observed, however long-term clear improvement of patients' symptoms has yet to be proven. Additional treatments are still at the experimental stage and their beneficial effect needs to be verified. The main research efforts in developing mitochondrial targeted therapy has been devoted to mitochondrial diseases. However, it is now generally accepted that treatment of

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chronic pathologies will benefit from mitochondrial treatments as well. Here we will review the different treatment approaches for mitochondrial diseases ranging from nutrient supplementation and exercise through pharmacological treatments to mitochondrial transplantation. We will describe their molecular targets and provide

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examples of their application in the treatment of chronic disorders. Molecular treatment such as mtDNA transfer into human oocytes carrying pathogenic mtDNA mutations (23), will not be discussed, for its current inapplicability in psychiatric

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disorders. Mitochondrial dysfunction has recently been considered as an important pathology in psychiatric disorders. Structural, molecular, genetic and functional alterations were reported and linked to neuronal activity and differentiation as well as to behavior in psychiatric patients-derived cells and animal models (16, 22, 24, 25). Mitochondrial targeted treatments as well as potential new treatment strategies in

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these disorders will be discussed.

Diet and nutrient supplementations:

Controlled diet and nutritional supplementation either individually or more commonly as a cocktail have been widely studied in patients with disturbances in

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energy metabolism and mitochondrial insufficiency, primarily in patients with mitochondrial diseases and neurodegenerative disorders (26–29). This treatment

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approach is based on accumulating evidence that nutrients can restore cellular energetic impairments. A positive correlation between age-appropriate body mass index (BMI) and mitochondrial ATP was observed in children with mitochondrial disorders and in severe malnutrition such as anorexia and starvation (30). Subjects suffering from severe malnutrition and from illness related Cachexia, a complex metabolic syndrome characterized by loss of muscle mass, show mitochondrial dysfunction including decreased oxidative phosphorylation (OXPHOS) capacity, disrupted mitochondrial dynamics and upregulation of mitochondrial uncoupling proteins (UCPs) (30–32). These finding together with data implicating pathological energy metabolism in many medical condition, led to the suggestion that controlled

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ACCEPTED MANUSCRIPT diet and nutrient supplementation associated with improve mitochondrial function, will alleviate disease symptoms in patients. High-fat diet was shown to induce beneficial effects on mitochondrial function in patients or animals with mitochondrial deficits. For example, ketogenic diet was shown to be effective in refractory epilepsy (33) and enhanced cellular metabolism and mitochondrial function in patients with mitochondrial disease as well as in chronic

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disorders with bioenergetics impairments (34). Clinical and preclinical studies show that ketogenic diet replenishes the CAC, thereby enhancing mitochondrial respiration. In addition, it was shown to affect neurotransmitters, specifically GABA, ion channels and signaling pathways such as the PPAR/PGC-1α, AMP activated

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protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) signaling, all involved in keeping the cellular bioenergetics homeostasis and play a role in neuroprotection (34–36). L-carnitine, which transports fatty acids into the

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mitochondrial matrix where they are subjected to ß-oxidation, has been also successfully used in mitochondrial pathologies and in aging, associated with low concentration of carnitine or impaired fatty acids oxidation (37, 38). Another approach is supplementation of mitochondrial cofactors to enhance ATP production. Examples for such natural supplements are reduced nicotinamide adenine dinucleotide (NADH), the substrate of the first complex (CoI) of the electron

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transport chain (ETC) and a redox cofactor in numerous cellular redox reactions. Additional supplements widely used in the treatment of chronic pathologies and mitochondrial diseases are coenzyme Q10 and α-lipoic acid. Q10 transfers electrons from complexes I and II to complex III and from the electron transfer factors, which

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accept electrons from fatty acid ß–oxidation. α-lipoic acid is a cofactor of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes of the CAC. These cofactors are also potent antioxidants and were shown to improve mitochondrial

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respiration, reduce symptoms, and disease progression and improve cognition in various pathological conditions such as diabetes, cancer, fibromyalgia, muscular cardiovascular diseases, neurodegenerative disorders and aging (26, 29, 39–41). Vitamins C, and E are known antioxidants and have been widely used as

natural supplements for different diseases and conditions including chronic disorders involving mitochondrial dysfunction such as cardiovascular, kidney and neurological diseases, mitochondrial diseases and aging. Riboflavin, a member of vitamins B family

(B2),

a

flavoprotein

precursor

which

active

forms

are flavin

mononucleotide (FMN) and flavin adenine dinucleotide (FAD), that function as cofactors for a variety of flavoproteine enzymes including CoI and CoII of the ECT, respectively. FAD is also required for acyl CoA dehydrogenase activity in fatty acid 5

ACCEPTED MANUSCRIPT oxidation and for glutathione reductase activity. Riboflavin treatment was shown beneficial for several mitochondrial disorders and stroke-like episodes (40, 42). All three vitamins improve OXPHOS activity. Studies in experimental models suggest the involvement of vitamins E and B2 in the assembly of CoI and of riboflavin in CoIV (43–46). Regarding clinical efficiency of controlled diet and nutrient supplementation

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there is still a debate between clinicians. Significant clinical responses have been definitely observed, yet at present, there are mixed evidence regarding their overall effectiveness. Several factors that may contribute to blunt the effect of such treatments are cocktail formulation, lack of match between cocktail ingredients and

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patient's medical state and duration of treatment. In addition, being natural these compounds can activate different cellular pathways that may not converge to induce the desirable clinical effect.

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Nutritional deficiency, particularly of omega-3 fatty acids, vitamins, minerals, and neurotransmitters amino acids precursors, has been reported to correlate with several psychiatric disorders (47). Clinical studies with daily supplement of these nutrients have shown improvements in patient's symptoms (48, 49) but their overall efficacy is still a matter of debate. Omega-3 polyunsaturated fatty acids, a major component of fish oil, has been extensively studied both in human and animal

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models of schizophrenia, bipolar disorder and major depression with mixed clinical outcomes, but a with tendency towards improvement (48, 50). In patients with heart diseases, however, omega-3 fatty acids long-term treatment had no significant effects on depressive symptoms (51). Among their multifarious effects these fatty

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acids were shown to induce reorganization of mitochondrial membranes composition, and enhancement of ADP sensitivity, ATP production, mitochondrial respiration and levels of the anti-apoptotic protein Bcl-2, all implicated in various psychiatric

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disorders (52, 53). Vitamins B supplementation has been shown by several clinical trials to improve mood, specifically depressive symptoms, as well as cognition in elderly patients (54). These vitamins have an essential role in mitochondria due to their involvement in the one-carbon transfer pathways and their anti-oxidative stress properties (55). The electron acceptor CoQ10 is used in the treatment of chronic fatigue, fibromyalgia and Parkinson's disease and was reported to have antidepressant effects in these diseases as well as in geriatric bipolar patients. In addition, lower CoQ10 plasma levels were observed in depression, particularly in patient with treatment resistant depression (56–58). In all, the use of nutrient or dietary supplements is very limited in psychiatry, although accumulating data have

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ACCEPTED MANUSCRIPT shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression, PTSD and suicidal behaviors (18). Exercise training: Exercise training has been recommended as medical treatment for improving life style, covering almost all human functions including cognition, attention, emotion,

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stress responses and physical state, in health, aging and disease. It has been suggested as a treatment for mitochondrial (59, 60) as well as chronic disorders with bioenergetics failure, including diabetes mellitus type I & II, cardiovascular, liver and musculoskeletal diseases, cancer and neurodegenerative disorders (61–65). Almost

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fifty years ago, it was shown that exercise increases mitochondrial protein mass, CAC activity and ATP production in muscles (66). Further studies in human and animals showed that exercise, both endurance and resistance, enhances

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mitochondrial biogenesis through activation of PPAR/PGC-1α signaling pathway and mitochondrial sensitivity to ADP in brain and periphery. Resistance exercise also activates mTOR and protein synthesis signaling, all adaptive signaling response of mitochondrial biogenesis (67, 68). Epidemiological studies show that exercise training, used as a single or add-on treatment, has a strong antidepressant action and therapeutic benefits in anxiety, affective and eating disorders, as well as in

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schizophrenia, bipolar disorder and dementia/mild cognitive impairment (69–71). However, the clinical effects of physical training on disease symptoms has not been systematically studied in psychiatry, maybe due to the low adherence of psychiatric patients to training regimen.

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Antioxidants:

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Pharmacological treatments:

Mitochondrial electron transport chain is one of the major sites of ROS

production in cells. Leakage of electrons mainly at CoI and CoIII leads to the reduction of oxygen to superoxide (O.2-), which is then converted to H2O2 by mitochondrial superoxide dismutase 1 (SOD1) or interacts with nitric oxide (NO) to produce peroxynitrite (ONO−2). H2O2 or O.2- can be further metabolized to highly reactive OH. free radicals that cause damage to nucleic acids, proteins and lipids (72, 73). In addition, ROS can initiate a cascade of events leading to apoptosis (74). Under physiological conditions, mitochondria, sensing cellular environmental changes and demands, produce ROS that serve as signaling molecules regulating various cellular processes including oxygen sensing, epigenetics, autophagy and cell

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ACCEPTED MANUSCRIPT proliferation (75, 76). Under pathological condition, mitochondrial ROS can cause mitochondrial dysfunction and cellular damage, underlying chronic pathologies, degenerative diseases, psychiatric disorders and aging (77–80). In order to prevent or reduce ROS-induced damage, cells and mitochondria have developed an antioxidant defense system, which includes enzymes such as catalase and glutathione reductase, reducing molecules such as NADH, molecules that chelate

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metals such as melanin and free radical scavengers such as GSH. Being a major cause for mitochondrial dysfunction and cellular damage, it is not surprising that the main line of treatment of mitochondria-associated disorders are antioxidants.

We have already discussed the natural antioxidants such as NADH, Q10, α-

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lipoic and vitamins C and E, which are used individually or in different combinations in the treatments of these diseases with varying efficiencies. Another strategy is to increase the levels of protective enzymes such as SOD1 or peroxidase in the

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mitochondria. An example for compounds that are radical scavengers and have SOD1 and catalase-like activities are the nitroxide compounds. These compounds specifically 2,2,6,6-tetramethylpyperidine-1-oxyl (TEMPO), were found beneficial in cell

cultures

and

experimental

models

of

different

diseases

including

neurodegenerative disorders, cancer, cardiovascular and kidney disorders, and aging related deficits (81, 82).

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In the 10-15 recent years, targeting of small molecules to the mitochondria is a major strategy in the development of treatments for mitochondria related disorders (83–85). One way of targeting a molecule to the mitochondria is the use of lipophilic cation conjugates, which will be concentrated in the mitochondria due to their larger

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negative membrane potential (-150mV to -180 mV) compared with the plasma membrane potential (-40 mV to -80mV) (86). Such lipophilic cation are decyltriphenylphosphonium and plastoquinon, which conjugation with CoQ is known as

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MitoQ and SkQ, respectively (87, 88). Conjugates of these molecules to the antioxidants CoQ, vitamins E and C were shown to reduce ROS and NO signaling in cell cultures, improve disease symptoms in animal models and are in clinical use as add-on treatment for mitochondrial diseases, chronic disorders and aging (28, 29, 86, 88–90).

Additional conjugates are natural compounds with a high affinity for the mitochondrial membrane. One such compound is hemigramicidin, a modification of gramicin S, a membrane-active cyclopeptide antibiotic. This compound has been conjugated to nitroxides such as TEMPO, and was shown to enhance mitochondrial function, prevent ROS formation and oxidation of cardiolipin, a protein essential for the optimal function of numerous enzymes involved in mitochondrial energy 8

ACCEPTED MANUSCRIPT metabolism, enhance survival and exerts neuroprotection in animal models and disease-derived cells (29, 91–94). The clinical use of TEMPO conjugates is still limited, yet there are ongoing clinical trial with TEMPO-1 in patients with minor stroke and with TEMPO-3:4 in autosomal dominant polycystic kidney disease, which have shown improvements of symptoms (95, 96). Szeto-Schiller (SS) peptides are mitochondria-targeted tetrapeptides, which

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uptake is not dependent on mitochondrial membrane potential and can thus be taken up by dysfunctional mitochondria (97). These antioxidant peptides reduce intracellular and mitochondrial ROS, inhibit mitochondrial permeability transition (MPT), their swelling, cytochrome c release and cell death. SS-31 (Bendavia)

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selectively binds to cardiolipin on the inner mitochondrial membrane, has protective effects during ischemia and ameliorates cardiomyopathy in heart failure animal models (98–100). SS-31 is under clinical trials for mitochondrial myopathy associated

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with genetically confirmed mitochondrial disease (86, 101).

Oxidative stress has been suggested as one of the mediators of brain functional impairment in schizophrenia, depression, anxiety and autism spectrum disorders, based on accumulating clinical and preclinical evidence of higher levels of oxidative markers and reduced levels of antioxidant defense markers in the brain and peripheral tissues (102–104). Clinical studies mainly used the antioxidant N-

substance

abuse,

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acetylcysteine (NAC) as add-on treatment in various psychiatric conditions including obsessive-compulsive

and

autism

spectrum

disorders,

schizophrenia, depression, and bipolar disorder. In schizophrenia, there are also reports on the use of vitamins E and C. From a systematic analysis of the literature, it

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is still not conclusive that antioxidant treatment has beneficial clinical effects in these disorders (103–105). However, the tolerability of these antioxidants and the positive

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outcomes observed in some of the studies calls for more comprehensive studies.

PGC-1α activating pharmacological drugs: PGC-1α is a transcriptional coactivator, regulating genes involved in energy

metabolism and is a master regulator of mitochondria biogenesis. It co-activates nuclear respiratory factor 1 and 2 (NRF1,2) and PPAR α, β, and γ among others. NFRs and PPARs then activate transcription of mitochondria structural and functional nuclear-encoded proteins including those involved in OXPHOS, fatty acid oxidation, mtDNA transcription, translation, and repair (106, 107). PGC-1α activity is enhanced by Sirtuin 1 (SIRT1) induced deacetylation or by its phosphorylation by several kinases, including p38/MAPK, glycogen synthase kinase 3β (GSK3β) and AMPdependent kinase (AMPK) (108, 109). Having such a major role in mitochondria 9

ACCEPTED MANUSCRIPT biogenesis it is not surprising that targeting PGC-1α and its upstream signaling cascade has become an attractive target for mitochondrial therapy. Different drugs that activate PGC-1α including 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), metformin, resveratrol, bezafibrate, and rosiglitazone, have been studied in experimental models mostly of mitochondrial diseases but also of chronic diseases, while several of them are also in clinical use (110, 111).

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AICAR is an analog of adenosine monophosphate (AMP) that stimulates AMPK activity (111, 112). It has been shown to be most effective in inducing mitochondrial biogenesis, OXPHOS-related gene transcription and respiratory chain complexes activities in fibroblasts of CoI deficient patients and CoIV deficient animal

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models (111, 113). AICAR has been used in clinical trials to treat diabetes type II, due to its antidiabetic properties and its ability to restore muscle and motor activity (114, 115). Metformin, which is widely used in diabetes type II and female infertility,

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activates AMPK among additional pathways, some of which include induction of mitochondrial stress and inhibition of CoI and mitochondrial shuttles (116–118). There is still a debate in the literature whether metformin is beneficial or detrimental for mitochondria (117).

Resveratrol, a natural phytoalexin found in a wide variety of plant species, activates PGC-1α indirectly through the activation AMPK and increases NAD+ levels,

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which leads to the activation of SIRT1, improves mitochondrial OXPHOS and enhances mitochondrial biogenesis (107). In animal models of obesity and neurodegenerative disorders such as Parkinson's, Alzheimer's and Huntington's diseases, resveratrol was shown to protect against obesity, insulin resistance and

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neurodegeneration (121). In psychiatric disorders, PPAR/PGC-1α function is still an enigma. Only one report hypothesized that brain PPAR-γ together with central insulin and the β-glucuronidase klotho, reduce ER stress and parainflammation, thereby

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interfering with stress responses in affective illness (122).

Inhibition of VDAC1 and TPSO The voltage-dependent anion channel 1 (VDAC1) is an outer mitochondrial

membrane protein and a convergence point for a variety of cell survival and death signals. It was recently shown that drugs inhibiting VDAC1 oligomerization, inhibit also apoptosis, and protect against mitochondrial dysfunction, including mitochondrial depolarization, ROS production and increase in intracellular Ca2+ concentrations. Two such novel compounds, VBIT-3 and more so VBIT-4, were recently shown to restore mitochondrial pro-survival properties by the inhibition

of VDAC1

oligomerization (123, 124). The translocator protein -18 kDa (TSPO) initially 10

ACCEPTED MANUSCRIPT characterized as the peripheral benzodiazepines binding site, complexes with the VDAC. It transports cholesterol into mitochondria for steroidogenesis, but has additional roles among them mitochondrial Ca2+ homeostasis and redox stress signaling

(125).

TSPO

expression

is

increased

in

brain

tumors,

and

neurodegenerative disorders mostly in peripheral tissues, but also in brain. TSPO expression and binding in peripheral cells has been observed in various psychiatric

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disorders such as anxiety, PTSD, depression, bipolar disorder, schizophrenia and panic disorder. Numerous TSPO ligands have been developed mostly to analyze TPSO expression as a biomarker, yet some have been suggested to have therapeutic potential in disease involving neuroprotection, neuroregeneration and

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anxiety (126).

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Mitochondrial transplantation:

The idea of transferring healthy mitochondria into cells has been suggested as an additional possible treatment for mitochondrial associated diseases. Mitochondria are dynamic organelles and can transfer in and between cells depending on cellular energy demands. They transfer between cells through various contact modes, including junction, cell fusion and tunneling nanotube formation, improving the injured recipient cells bioenergetic state and even rescuing them. One

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example is the rescue cardiomyoblasts from cell death by mesenchymal stem cells in an in vitro ischemia model via direct cell-to-cell connections (127–133). Transfer of mitochondria between cells occurs also in-vivo resulting in beneficial bioenergetics effects and protection against injury. For example, bone marrow-derived stromal cells

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were shown to increase alveolar ATP levels and protect against acute lung injury, by transferring mitochondria through gap junctional channels formed with the alveolar

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epithelia. In an animal model of transient focal cerebral ischemia, functional mitochondria released by astrocytes entered neurons and enhanced cell survival signals (134–136).

An additional strategy that has been suggested is transfer of isolated

mitochondria.

The ability of

isolated autologous,

alogenic

and xenogenic

mitochondria to enter cells without any manipulation, stay functional, increase OXPHOS activity and recover cell from injury has been shown in various cell cultures including cell depleted from their mtDNA (ρ(0) cells), fibroblasts of patients with CoI mutation, cardiomyoblasts and differentiating human induced pluripotent stem cells (hiPSC) (25, 137–141). Several studies suggest that mitochondria enter cells by an actin-dependent macropynocytosis, however the specific mechanism and the 11

ACCEPTED MANUSCRIPT endocytosis pathway are still unclear (139, 140, 142). A few studies also showed invivo beneficial effects of isolated mitochondrial transplantation. For example, in animal models of myocardial ischemia and reperfusion and of Parkinson's disease, isolated mitochondria enhanced myocardial post-ischemic functional recovery and cellular viability and attenuated neurotoxicity, respectively (141, 143).

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Mitochondrial transplantation is still experimental and has been studied in models of ischemia/reperfusion and neurodegeneration. We have studied both invitro and in-vivo the effect of transplantation of isolated active normal mitochondria (IAN-MIT) on schizophrenia-related mitochondrial dysfunctions and behavioral responses. Our data show that IAN-MIT transplantation improves mitochondrial

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function including respiration, mitochondrial membrane potential (∆ψm) and mitochondrial network dynamics concomitant with enhancement of

differentiation

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into neurons in schizophrenia-derived iPSCs (16, 25, 144). In-vivo, intra-medialprefrontal cortex transplantation of IAN-MIT in animal model of schizophrenia (145, 146) in adolescence, prevented mitochondrial ∆ψm dissipation, the main driving force for ATP production, and attentional deficit at adulthood (25). To the best of our knowledge, this is the only study of isolated mitochondrial transplantation in

Conclusions:

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experimental models of psychiatric disorders.

Psychiatric disorders are not congenital mitochondrial disorders, yet mitochondrial dysfunction is probably an important pathology in these disorders. In addition, psychotropic medication including antidepressants, mood stabilizers and

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antipsychotic drugs interact with mitochondrial various targets including the OXPHOS complexes, the outer mitochondrial membrane proteins VDAC1, monoamine oxidase

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(MAO) and the anti-apoptotic protein Bcl2 (147–149). In mitochondrial related diseases including psychiatric disorders, accumulating evidence support beneficial effect of mitochondrial targeted treatments including dietary, nutritional supplements, antioxidants and PGC-1α activating drugs. Considering them as an alternative or add-on treatment in psychiatric disorders, could be beneficial for patients, specifically as non-adherence and resistance to current psychotropic drugs is not uncommon in psychiatry. However, targeting mitochondria can be intricate as mitochondria are two edges sword that can also induce oxidative stress and apoptosis leading to neuronal deficits and even death. In line with the latter are our findings of intra-cortically transplantation of IAN-MIT aversive effects on mitochondrial function and behavioral response impairments in healthy rats, opposite to their restore of function in 12

ACCEPTED MANUSCRIPT schizophrenia model rats (25). Similarly, into substantia nigral unilateral IAN-MIT transplantation in a parkinsonian rat model increased rotation and decreased striatal levels of dopamine and its metabolites (unpublished data). Therefore, intensive research is needed in psychiatric disorders for each treatment approach described in this review to avoid malfunctioning of the mitochondria. Tailoring the various existing supplements and drugs to the various psychiatric conditions, as well as identifying

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novel mitochondrial targets more relevant to psychiatric disorders and brain bioenergetics, are examples for future research lines and challenges. Such novel targets can be enzymes of the glycolysis pathway and CAC cycle among them hexokinase

1,

succinate

dehydrogenase

and

malate

dehydrogenase,

as

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metabolomics studies suggest their involvement in several psychiatric disorders including bipolar disorder and schizophrenia (150). Figure 1 summarizes different mitochondrial targets and approaches of current and potential therapeutic

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intervention. Any intervention with mitochondrial function will have to take into account the homeostasis in cell-mitochondria cross talk processes. Nevertheless, the fundamental role of mitochondria in neuronal activity, sprouting, plasticity, survival and development, turns them into an attractive treatment target in psychiatric disorders.

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Acknowledgements

This work was supported by grant from the Israel Science Foundation-ISF (1517/15).

of interest.

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References:

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Disclosures: All authors report no biomedical financial interests or potential conflicts

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ACCEPTED MANUSCRIPT Legend to the figure: Figure 1: Various experimental and therapeutic approaches targeting mitochondria. Potential therapeutic compounds and their targeted mitochondrial pathways are illustrated. Doses and cocktail composition of the various supplements or additional mitochondrial targets needs to be substantiated to enable a safe clinical use for the

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benefit of patients with mental disorders. A. Factors mainly activating mitochondrial biogenesis through activation of PGC-1α, the master transcription factor of mitochondrial genes. B. Nutrients in clinical use that increase CAC activity, ATP production, mitochondrial biogenesis and/or are antioxidants. C. Antioxidants that either scavenge ROS, increase the activity of enzymes-protecting oxidative damage

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or modulate mitochondria redox state. D. Drugs that inhibit VDAC1 oligomerization and thereby apoptosis. E. Mitochondrial transfer and transplantation as a tool to

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restore mitochondrial function. F. Psychotropic drugs interacting with various mitochondrial sites. Acetyl

(Ac),

5-Aminoimidazole-4-carboxamide

ribonucleotide

(AICAR),

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activated protein kinase (AMPK), catalase (CAT), citric acid cycle (CAC), decyltriphenylphosphonium-CoQ (MitoQ), glutathione peroxidase (GPX), monoamine oxidase (MAO), oxidative phosphorylation system (OXPHOS), peroxynitrite (ONO−2),

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peroxisomal proliferator activator receptors (PPAR), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), plastoquinon-CoQ (SkQ), nuclear respiratory factor (NRF), sirtuin 1 (SIRT1), superoxide dismutase (SOD1), 2,2,6,6tetramethylpyperidine-1-oxyl (TEMPO), Translocator protein (TSPO), voltage-

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dependent anion channel 1 (VDAC1).

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