Succinate dehydrogenase: Prospect for neurodegenerative diseases

Succinate dehydrogenase: Prospect for neurodegenerative diseases

Accepted Manuscript Succinate diseases dehydrogenase: Prospect for neurodegenerative Mohammad Jodeiri Farshbaf, Abbas Kiani-Esfahani PII: DOI: Re...

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Accepted Manuscript Succinate diseases

dehydrogenase:

Prospect

for

neurodegenerative

Mohammad Jodeiri Farshbaf, Abbas Kiani-Esfahani PII: DOI: Reference:

S1567-7249(16)30241-0 doi:10.1016/j.mito.2017.12.002 MITOCH 1246

To appear in:

Mitochondrion

Received date: Revised date: Accepted date:

9 November 2016 25 November 2017 6 December 2017

Please cite this article as: Mohammad Jodeiri Farshbaf, Abbas Kiani-Esfahani , Succinate dehydrogenase: Prospect for neurodegenerative diseases. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Mitoch(2017), doi:10.1016/j.mito.2017.12.002

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ACCEPTED MANUSCRIPT Succinate dehydrogenase: prospect for neurodegenerative diseases Mohammad Jodeiri Farshbaf*1 , Abbas Kiani-Esfahani2 1

Department of Biology, New Mexico State University, Las Cruces, New Mexico, USA.

*Corresponding author: Mohammad Jodeiri Farshbaf ([email protected]). Department of Biology, New Mexico State University, Las Cruces, New Mexico, USA. 2

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Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, 816513-1378, Iran.

ACCEPTED MANUSCRIPT Abstract Onset of Alzheimer's, Parkinson's and Huntington's diseases as neurodegenerative disorders is increased by age. Alleviation of clinical symptoms and protection of neurons against degeneration are the main aspects of researches to establish new therapeutic strategies. Many studies have shown that mitochondria play crucial roles in high energy demand tissues like

Succinate dehydrogenase (SDH) connects tricarboxylic cycle to the

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stress and degeneration.

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brain. Impairments in mitochondrial activity and physiology can makes neurons vulnerable to

electron transport chain. Therefore, dysfunction of the SDH could impair mitochondrial

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activity, ATP generation and energy hemostasis in the cell.

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Exceed lipid synthesis, induction of the excitotoxicity in neurodegenerative disorders could be controlled by SDH through direct and indirect mechanism. In addition, mutation in SDH

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correlates with the onset of neurodegenerative disorders. Therefore, SDH could behave as a key regulator in neuroprotection. This review will present recent findings which are about

we

will discuss

about

all possibilities

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Additionally,

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SDH activity and related pathways which could play important roles in neuronal survival. which

candidate

SDH

as a

neuroprotective agent.

Succinate

dehydrogenase,

Neurodegenerative

disorders,

mitochondria,

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Keywords:

neuroprotection, lipid synthesis, excitotoxicity.

Abbreviations: ΔΨ, Mitochondrial membrane potential; Aβ, Amyloid beta; AD, Alzheimer's disease; AMPA, α-amino-3-hydroxy-5- methylisoxazole-4-propionate; ApoE/D, Apolipoproteins E/D; BBB, Blood brain barrier;; GSH, HIF-1α,

glutathione; HD, Huntington's disease; H2 O2 , hydrogen peroxide;

hypoxia inducible factor 1α; JNK, c-Jun N-terminal Kinase;; LDs, lipid droplets;

ACCEPTED MANUSCRIPT mHtt, mutant huntingtin protein; mtDNA, phenylpyridinium;

MPTP,

mitochondrial DNA; MPP+, 1-methyl 4-

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;

mPTPs,

Mitochondrial permeability transition pores; mTOR, mammalian target of rapamycin; NMDA, N-methyl-D-aspartate; NO, Nitric oxide; NOS, nitric oxide synthetase; O2·−, Superoxide anion radical; ·OH, hydroxyl radical; ,ONOO-, peroxynitrite; PD, Parkinson's

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disease; ROS, reactive oxygen species; PINK1, PTEN-induced putative kinase 1; SDH,

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succinate dehydrogenase; SOD2, superoxide dismutase manganese type; SOD1, superoxide

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dismutase Cu-Zn type; succinate: SQR, ubiquinone oxidoreductase; SREBP,

sterol

regulatory element binding protein; TCA, tricarboxylic acid; VDAC, Voltage-dependent

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anion channels.

ACCEPTED MANUSCRIPT Introduction

Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) are the most prevalent neurological diseases in aged people. High cost of treatment and prevalence of these neurological disorders in developed countries, guide

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studies to find out cues to prevent neuronal death.

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Neurodegenerative diseases as multifactorial disorders depend on various cellular mechanism such as mitochondrial dysfunction, neuroinflammation, glutamate excitatory, oxidative stress,

Mitochondrial dysfunction and lipid accumulation in the brain have close cross

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autophagy.

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disruption in iron hemostasis and lipid synthesis, protein aggregation and failure of

talking with each other during neurodegeneration (Jodeiri Farshbaf et al., 2016b; Schwall et

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al., 2012). disruption in lipid hemostasis which is caused lipid accumulation in the brain could be hallmark for some neurological diseases (Walter& Echten-Deckert, 2013; Kim et al., Intracellular lipid droplets (LDs) are the dynamic organelles which store lipids such

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2015).

as triacylglycerol and cholesterol esters and more intense in the adipose tissue (Greenberg et

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al., 2011). In neurodegenerative disorders high amount of ROS triggers lipid accumulation in neurons (Liu et al, 2015). Transportation of lipids in nervous system is regulated by Cellular stress, including

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apolipoproteins E and D (ApoE, D) (Huang and Mahley 2014).

inflammation and oxidative stress have potential roles in LDs biogenesis and formation (Khatchadourian et al., 2012; Younce& Kolattukudy, 2012). Therefore, LD formation could be the biomarker for neurodegeneration by the presentation of clinical symptoms (Liu et al, 2015). In this review, we document that focusing on the mitochondrial complex II could reveal new targets for therapeutic drug development for neurodegenerative disorders because of its potential in lipid metabolism.

ACCEPTED MANUSCRIPT Mitochondria and neurodegeneration: Contribution of the mitochondrion to the neurodegenerative disorders such as AD, PD and HD candidates this organelle as therapeutic target.

Mitochondria have their own circular

DNA with 16,569 base pairs. Some components of the respiratory system, specific rRNA and tRNA are encoded by mtDNA (Lin & Beal, 2006).

Mitochondria have wide ranges of

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physiological and cellular properties such as maintaining intracellular Ca2+ homeostasis, lipid

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oxidation, ATP production, reduction-oxidation potential of the cell and apoptosis which all

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of them relevant to neurodegenerative disorders (Martin 2010; Nicholls 2002). Brain by having 2% of body weight uses 20% of oxygen consumption. ROS attacks lipids,

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DNA and protein in the neurons and causes neurodegeneration. Superoxide anion radical

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(O2·−), hydroxyl radical (·OH), non-radical oxidants such as H2 O2 are categorized as ROS. Superoxide has the highest capacity of oxidation in the cell (Petlicki & van de Ven,1998).

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Mitochondria is the main sources of the superoxide generation. Oxygen reaction with the electrons which are leaked from mitochondrial respiratory chain is the main reaction for

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production of the superoxide (Loschen et al., 1974). Superoxide dismutase (SOD) catalyzes dismutaion of superoxide radical to hydrogen peroxide (Fukai & Ushio-Fukai, 2011). Mn-

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dependent isoform (Mn SOD, SOD2) which is in the mitochondrial matrix (Weister & Fridovich, 1973).

Complex I and III of the respiratory chain are the main sources of the

ROS generation (Mailloux 2015). Nitric oxide (NO) is synthesized by conversion of the L-arginine to NO and L-citrulline through reaction which is catalyzed by nitric oxide synthetase (NOS) (Knowles & Moncada, 1994). NO as an important molecule not only play a role as second messenger but also binds to cytochrome c oxidase and decrease its affinity to oxygen. Binding of NO to cytochrome c oxidase affects ATP production and electron flux (Moncada & Bolanos, 2006). In addition,

ACCEPTED MANUSCRIPT inhibiting the respiratory chain by NO elevates superoxide and hydrogen peroxide levels. In the high level the NO, superoxide is converted to peroxynitrite (ONOO -) rather than hydrogen peroxide (Poderos et al., 1998). So, excessive amount of NO contributes to neurological diseases (Dawson & Dawson, 1996). NO has ability to influence the function of respiratory chain and causes mitochondrial dysfunction. Incubation of the brain mitochondria

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with ONOO - shows loss of activity in complex IV (Bolanos et al., 1995). Cardiolipin as the

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most abundant phospholipid in mitochondrial inner membrane, is peroxidized when complex

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IV loose its activity (Soussi et al., 1990). Moreover, exposure of the brain mitochondria to ONOO- decrease complex II activity as well (Brookes et al., 1998). NO prevents protein

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normal function and charcter through nitrosylation process. Sulfhydryls as main group of the active site in many enzymes are targeted by NO which changes protein function (Radi et al., Mitochondrial permeability transition pores (mPTPs) are channels in the contact site

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1991).

of the inner and outer membranes of the mitochondria. They are responsible for Ca2+

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hemostasis in non-pathological condition. But in the presence of the oxidative stress, ATP depletion and overloaded Ca2+ opening of these channels releases pro-apoptotic proteins into

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the cytoplasm (Brenner & Grimm, 2006). ONOO- is one of the main molecules which can trigger mPTP opening under pathological conditions (Chavez et al., 1997). In AD, PD and

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HD peroxynitrite has crucial role through nitrosylation of proteins, opening of the mPTP and impairment of the mitochondrial activities especially electron transport chain (Asiimwe et al., 2016; Jiménez-Jiménez et al., 2016; Jamwal & Kumar, 2017).

In neurodegenerative disorders neurons are excited by enormous ionic flow which induces mitochondrial dysfunction and apoptosis. Glutamate as the main excitatory neurotransmitter, is released excessively in these diseases. Glutamate acts through N-methyl-D-aspartate (NMDA)

receptor and

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

(AMPA)

ACCEPTED MANUSCRIPT receptors (Hara & Synder, 2007). In AD, amyloid beta (Aβ) increases excitatory by influencing NMDA receptors indirectly (Deng et al., 2014). Moreover, in AD glutamate reuptake from the synaptic cleft is decreased because of Aβ (Scimemi et al., 2013). Previous studies showed that agonists for NMDA receptor increases neurodegeneration in the striatum like HD (Coyle and Schwarcz, 1976). NMDA receptors are more active in various HD mouse

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models (Shehadeh et al., 2006). Accumulation of glutamate in the synaptic cleft and over

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activity of NMDA receptors was reported in PD (Zhang et al., 2016). NMDA activation by

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glutamate not only excites postsynaptic neurons but also increase Ca 2+ influx into the cell (Zipfel et al., 2000). Mitochondria buffer cytoplasmic Ca2+ primarily by using uniporters

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which are opened in the high concentration of Ca2+ (Rizzuto et al., 2000). Influx of the Ca2+ into the mitochondrial matrix depends on the electrochemical gradient. Mitochondrial

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membrane potential (ΔΨ) is generated by respiratory chain during oxidative phosphorylation (Sparagna et al., 1995). In neuronal cells preventing Ca2+ uptake by mitochondria protects

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them against injuries and degeneration (Stout et al., 1998). Mitochondrial Ca2+ overload increases ROS production, decrease or complete loss of ΔΨ, opening of the PTP, disrupts

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mitochondrial activity and finally ATP depletion (Giorgi et al., 2012). Some studies showed crosstalk between Ca2+ hemostasis and neurodegeneration. For example, in AD model Aβ

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inserts into the plasma membrane and increase Ca2+ influx into the cytoplasm by acting as ion channel (Demuro et al., 2000). Moreover, Aβ oligomer causes mitochondrial Ca2+ overload. Excessive Ca2+ in mitochondria elevates ROS generation, inhibits ATP production and triggers apoptosis by releasing cytochrome c (Brustovetsky et al., 2003). Like AD, in PD models accumulation of α-synuclein increases Ca2+ influx into the neuron (Furukawa et al., 2006). PTEN-induced putative kinase 1 (PINK1) is a mitochondrial protein which shows PD etiology in the mutant form. Some evidences show that in the PINK1 deficient mouse, mitochondria are sensitive to Ca2+ in dopaminergic neurons (Akundi et al., 2011). HD is

ACCEPTED MANUSCRIPT characterized by the neurodegeneration in striatum. Abnormal expansion of poly glutamine (Poly Q) in Huntingtin protein (Htt) is the main reason of HD. Mutant form of the huntingtin (mHtt) makes neurons vulnerable to Ca2+ overloading which leads to apoptosis and degeneration of neurons (Choo et al., 2004). Mitochondria play crucial role in the cytoplasmic Ca2+ buffering and overloading of the mitochondria with Ca2+ not only disrupt function

but

also

triggers

other

signaling

pathways

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mitochondrial

which

leads

to

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neurodegeneration. Mitochondrion has distinct DNA (mtDNA) which encodes some proteins

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of respiratory chain and specific rRNA and tRNA for mitochondria. Human mtDNA is double strands circular molecule with approximately 16.6 base pairs which encodes 2 rRNA, et

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22 tRNA and 13 polypeptides of the respiratory chain (Eichner & Giguère 2011; Legros

al., 2004). Complex I (NADH CoQ dehydrogenase) contains 45 subunits which seven of

tetrahydropyridine

(MPTP),

or

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them are encoded by mtDNA (Davis & Williams 2012). 1-methyl 4- phenyl 1,2,3,6 more

specifically

its

active

metabolite 1-methyl 4-

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phenylpyridinium (MPP+) inhibits complex I in dopaminergic neurons which leads to degeneration of dopaminergic neurons (Langston & Ballard 1983; Jodeiri Farshbaf et al.,

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2016a). Previous studies showed PD and HD patients have inactive complex I in their platelets (Haas et al., 1995; Silva et al., 2013). In addition to neurotoxins such as MPP+,

al., 2006).

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deletion in mtDNA is provided in the dopaminergic neurons of the PD patients (Kraytsberg et

degraded mtDNA and low expression of complex I subunits are defined in early and definite AD brain specimens (Yan et al., 2013; Manczak et al., 2004). Complex II (succinate dehydrogenase (SDH) or succinate: ubiquinone oxidoreductase (SQR) has 4 subunits which all of them are encoded by nuclear DNA. Studies showed mitochondrial complex II defect and lower activity in AD, PD and HD patients (Long et al., 2012; Hattori et al., 1991; Damiano et al., 2013). Complex III (Ubiquinol: cytochrome c oxidoreductase) has 11

ACCEPTED MANUSCRIPT subunits and one of them is encoded by mtDNA. In AD models this complex is inhibited by Aβ (Devi & Anandatheerthavarada 2010). Recent studies showed that mutations in complex III subunits can be caused striatal atrophy in HD (Gu et al., 1996). Complex IV (cytochrome c oxidase) comprises 12 subunits that 3 of them are derived from mtDNA. α- synuclein as the main misfolded protein in PD can impair complex IV activity and function (Martin et al.,

in AD patients, Aβ inhibits activity of the

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complex IV activities (Benecke et al., 1993).

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2006). In addition, previous studies showed platelets of PD patients had aberrations in

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cytochrome c oxidase as well as HD model (Casley et al., 2002; Tabrizi et al., 2000) (Figure1).

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Irregularities in activities of electron transport chain not only cause ROS generation but also show ATP depletion. Neurons depend on mitochondrial activites because of their high energy

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demand nature, for example activity of synapse needs to use high energy which is supplied

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by mitochondria (Jodeiri Farshbaf et al., 2016b)

In summary, neurodegenerative diseases associated with mitochondrial dysfunction. A

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strategy of therapies should be considered specific strategies which lead to increased

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mitochondrial activities and efficiencies.

Succinate dehydrogenase/ succinate: ubiquinone oxidoreductase Structure and function

Succinate dehydrogenase (SDH) is the smallest member of mitochondrial respiratory chain and it ties tricarboxylic acid (TCA) cycle and the respiratory chain (Cecchini 2003). SDH is the only complex of the respiratory chain which is encoded by nuclear DNA entirely. Moreover, SDH never pump proton across mitochondrial inner membrane during oxidative phosphorylation. Structure of the SDH shows hydrophilic tail in the matrix, hydrophobic part

ACCEPTED MANUSCRIPT which is embedded in the mitochondrial inner membrane and short tail in mitochondrial inner membrane space (Sun et al., 2005). It has four subunits (SdhA, SdhB, SdhC and SdhD) And all subunits are encoded by nuclear DNA (Grimm 2013). They are located on different chromosomes, sdha on chromosome 5, sdhb and sdhc on chromosome 1 and sdhd on chromosome 11. SdhA (flavoprotein) and SdhB (Fe-S protein) are two soluble subunits of the

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SDH while SdhC and SdhD are integral parts of the complex, bond it to inner mitochondrial

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membrane (Sun et al., 2005). SDH has two active sites for oxidation of succinate to fumarate

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in TCA cycle and reduction of quinone. SdhA is the subunit for succinate conversion to fumarate (Hägerhäll 1997). SdhB with 3 Fe/S centers in its structure mediates electron

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transferring to ubiquinone through in succinate oxidation (Guo & Lemire 2003) (Figure2).

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Succinate dehydrogenase regulation

TCA cycle provides not only electron to mitochondrial transport chain but also precursors for Various circumstances influence SDH activity:

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synthesis of the substances like amino acids.

concentration of malate, fumarate, citrate and specifically oxaloacetate and hydrogen

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peroxide are the known factors which impacts on SDH activity (Gutman et al., 1971; NultonPersson & Szweda 2001). Also, SDH activity and glutathione (GSH) level is associated in

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human melanoma cells (Guo et al., 2016). pathological issues.

Mutation

in

SdhA

causes

Mutations in the SDH subunits causes Leigh

Syndrome

as a progressive

neurodegenerative disorder (Parfait et al., 2000). In addition, defects in SdhB, C and D correlates with paraganglioma, neuroendocrine neoplasm (Niemann & Muller 2000) (Table 1). Inhibition of succinate dehydrogenase leads to malate and

fumarate accumulation in the cell

(Van Vranken et al., 2014). For ATP generation cells need low concentration of fumarate (Rottenberg & Gutman 1977), therefore, high level of fumarate in matrix can decrease ATP

ACCEPTED MANUSCRIPT production. Furthermore, accumulation of succinate in the cell is the main provokes of the ROS generation (Ralph et al., 2013). SDH is capable to modulate generated superoxide by other complexes, I and III, of electron transport chain (Drose et al., 2011). Succinate can move easily through dicarboxylic acid translocator and Voltage-dependent

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anion channels (VDAC) between mitochondria and cytosol. SDH inhibition increases succinate level which moves into the cytosol and increase stability and activity of the hypoxia Transcriptional activity of the HIF1α

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inducible factor 1α (HIF1α) (Selak et al., 2005).

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decreases mitochondrial biogenesis in the cell HIF-1α is one of the main factors that decrease mitochondrial biogenesis (Zhang et al., 2007) So, beside ROS generation and hemostasis,

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SDH has ability to influence mitochondria density.

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TCA cycle is the main source for the precursors of the many metabolites as well as fatty acids and sterol which can control various cellular signaling (Owen et al., 2002).

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Succinate dehydrogenase and related signaling pathways

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Lipids can be categorized in eight groups: fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides. Circulating lipids and cholesterol never pass blood brain barrier (BBB) and de novo lipogenesis is pivotal for

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brain (Camargo et al., 2009).

During aging and in pathological conditions lipids accumulate

in the brain in the form of lipid droplet (Shimabukuro et al., 2016).

lipid droplet

accumulation in the brain is the prior hallmark of neurodegeneration. sterol regulatory element binding protein (SREBP) is the main regulator of lipid biogenesis in the cell (Horton et al., 2002).

SREBP is a helix-loop-helix leucine zipper transcription factor that can

translocate into nucleus after activation SREBP (precursor) is synthesized and bind to endoplasmic reticulum (ER) (Sakakura et al., 2001). Upon activation, SREBP (precursor) is cleaved and active domain of it (N-terminal) translocate into the nucleus (Eberlé et al., 2004).

ACCEPTED MANUSCRIPT SREBP controls the expression of various genes which are related to lipogenesis (Porstmann et al., 2008). Mitochondrial dysfunction triggers lipid accumulation in the glial cells and activates SREBP (Liu et al., 2015). In chronic neurodegeneration, SREBP translocation into the nucleus is increased (Cincioglu et al., 2012). While in Drosophila low SREBP level protects neurons against degeneration and lipid accumulation (Liu et al., 2015). Expression

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level of SREBP is changed in hypothalamus or cerebrum through aging (Okamoto et al.,

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2006). Also, active SREBP mediates neuronal death through NMDA receptors and excitatory

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state (Taghibiglou et al., 2009). The mammalian target of rapamycin (mTOR) activates SREBP for lipid synthesis (Duvel et al., 2010). mTOR is a 289-kDa serine/threonine protein

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kinase that represents sensor of nutrients in the cell. It has two distinct complexes: mTORC1 and mTORC2. In Drosophila inhibition of mTOR by rapamycin increases SDH activity

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(Villa-Cuesta et al., 2014). In neurodegenerative disorders mTOR play central role. Recently, targeting mTOR for therapeutic approaches validates the role of this molecule in drug

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development for neurodegenerative diseases (Maiese, 2016). Mitochondrial defects and oxidative stress induce c-Jun N-terminal Kinase (JNK) signaling pathway. In AD, PD, and

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HD JNK is in active form (Zhou et al., 2015; Dagda et al., 2009; Taylor et al., 2013). Activation of JNK in responses to stress causes expression of various genes which induce

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apoptosis (Gupta et al., 1996; Bonny et al., 2005; Borsello & Forloni 2007).

Succinate

induces JNK phosphorylation in retinal ganglion cell line, RGC-5 (Hu et al., 2015). Therefore, we could conclude that beside oxidative stress, SDH deficiency which can elevate succinate concentration influences JNK phosphorylation. Succinate dehydrogenase and neurodegenration Inhibition of SDH leads to loss of striatal neurons and symptoms of HD (Tunez et al., 2010). Malonate is another inhibitor of the SDH can cause neuronal injuries and degeneration (Beal et al., 1993). Mechanism of neurodegeneration in the presence of malonate is happened not

ACCEPTED MANUSCRIPT only by secondary excitotoxicity but also by mitochondrial membrane potential collapse and cyt C releasing (Fernandez-Gomez et al., 2005) .

Interestingly, SDH is the only subunit of the electron transport chain which is encoded by

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nuclear genome. It bonds TCA cycle to oxidative phosphorylation. Previous studies showed that during neurodegeneration lipids accumulate in the brain which could be the biomarker

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for diagnosis. Fatty acids and sterol are the intermediate metabolites of the TCA and their

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hemostasis could be influenced by SDH activity easily. Moreover, alteration in lipid synthesis

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pathway, mTOR and SREBP, could be affected by SDH activity and function. Future Direction

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There are many evidences that SDH is the main source of the ROS generation in the mitochondria. Most subunits of the complexes in electron transport chain are encoded by

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nuclear and mitochondrial genomes while SDH is the only complex that is encoded by

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nuclear genome completely. Through coupling TCA cycle and oxidative phosphorylation, any change in SDH activity or assembly can influence the concentration of metabolites in TCA.

Studies show mutation in SDH subunits and

inhibition its activity triggers

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neurodegeneration in brain. SDH bonds with various signaling pathways indirectly and one of them is mTOR/SREBP which play crucial role in the lipid synthesis. SDH regulates mTOR/SREBP directly and indirectly. For example mTOR inhibits the activity of the SDH which leads to low fatty acid oxidation and lipid accumulation. Net results from previous studies candidate SDH as an effective target for therapeutic interventions in neurological diseases and aging. Increasing the activity of SDH can control lipid overloading and excitotoxicity and NMDA dependent signaling in neurodegenerative disorders. Identification and characterization of the SDH protein provides important new insights into the mechanisms

ACCEPTED MANUSCRIPT which SDH protects neurons from lipid overloading and ROS generating, and it can be therapeutic candidate to ameliorate neurodegeneration. Conflict of interest None of the authors has any conflicts of interest to disclose and all authors support

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submission to this journal

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Figure legends: Figure1: Abnormalities in activities of the electron transport chain can cause various types of

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neurodegenerative disorders (AD, PD and HD). Main outputs of impaired oxidative

Figure 2: Structure of SDH. Four subunits participate in electron transportation from

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Table 1. Summary of SDH mutations and related disorders

PGL1

PGL3

PGL4

SDH Gene

SdhD

SdhC

SdhB

Leigh Syndrome SdhA

Chromosomal Location

11q23

lq2l

lp35-36.l

5p15 and 3q29

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PGL= paraganglioma

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Neurodegenerative diseases correlate with various factors such as: mitochondrial deficiency, ROS generation etc.



Succinate dehydrogenase is the only subunit of the electron transport chain which is encoded by nuclear genome entirely. Succinate dehydrogenase bonds oxidative phosphorylation to TCA cycle

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