Types of Mitochondrial Diseases
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Mitochondrion is the primary site of energy and ATP generation so it is called “power house” of the cell. Mitochondria are composed of two different types of membranes like an outer membrane, an inner membrane and a protein-rich matrix. Protein kinases can localize to specific cytoplasmic sub compartments and mediates many important processes like cell motility and many signaling events. The mitochondrion is a point of integration for these signaling cascades due to its role in cellular metabolism, redox processes, and cell survival-death. PI3K/Akt/Protein Kinase B(PKB) ,Protein kinase C(PKC),Raf-MEK-ERK,JNK/SAPK and p38 MAPK, Apoptosis signal-regulating kinase 1 (ASK1),Glycogen synthase kinase 3β (GSK-3β),Protein kinase A (PKA),PTEN-induced kinase 1 (PINK1) are associated with mitochondria and modulate mitochondrial activity and the release of mitochondrial products affects mitochondrial respiratory chain, transport, fission-fusion events, calcium turnover, reactive oxygen species (ROS) production, mitochondrial autophagy and apoptotic cell death. Mitochondrial diseases are due to degeneration of the mitochondria in specialized compartments present in every cell of the body. Mitochondria diseases causes damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems. So this review focuse on various kinases associated with mitochondria, their role in progression of neurodegenerative diseases and treatment.
Mitochondrion is present in every eukaryotic cell having size range of 0.5 to 10 μm in diameter (Munn et al., 1974). It is the primary site of energy and ATP production so it is called “power house” of the cell. Mitochondria are composed of two different types of membranes like an outer membrane, an inner membrane and a protein-rich matrix. The molecular machinery of chemiosmosis is associated with the inner membrane. Mitochondrial energy production is same in all cells but there are variations in shape, connectivity, and membrane morphology (Munn et al., 1974, Fawcett et al., 1966). There might be changes in the “energization” state of the mitochondrial membrane integral to energy production (Green et al., 1973). Structural diversity and dynamics of mitochondria were studied with the help of light and electron microscopy and their relationship with other cellular components. This technique gives idea about changes in shape and structure of mitochondria during biological processes. Electron tomography shows remodeling of the inner membrane in the case of apoptosis and cytochrome c release (Scorrano et al., 2002) and mitochondrial fragmentation (Sun et al., 2007). Cell controls the mitochondrial structure, its function and response against various stimuli (Mannella et al., 2006)
A mitochondrion has double layer structure composed of phospholipids and proteins (Munn et al., 2007). These two double membranes have five compartments like the outer membrane, the intermembrane space ( between the outer and inner membranes), the inner membrane, the cristae formed by unfolding of the inner mitochondrial membrane, and the matrix (space in the inner mitochondrial membrane).
1.2 Inner Mitochondrial membrane:
The inner membrane contains invaginations called cristae. The cristae are not random folds but these are small regions that open through narrow tubular channels into the peripheral region of the membrane (Fig. 2) (Mannella et al., 2001).
Topographic analysis of intact, frozen-hydrated, rat liver mitochondria(Mannella et al., 2001) describes the inner diameter of the tubular “cristae junctions” is 10-15 nm (Fig. 2).This is enough to pass metabolites and many soluble proteins and the inner membrane restrict internal diffusion rates. For example, computer simulations indicate that the steady-state level of ADP inside cristae with long small junctions can drop below the Km for the adenine nucleotide translocator, leading to a local drop in ATP generation. Like that truncated (t)-Bid-induced remodeling in the inner mitochondrial membrane of isolated mouse liver mitochondria (Fig. 2) causes mobilization of a large fraction of the internal pool of cytochrome c lead to increased rates of reduction by the NADH cytochrome b5 redox system on the outer membrane of the organelle(Scorrano et al.,2002).The inner-membrane remodeling involves fivefold widening of the cristae and diffusion of cytochrome c between intracristal and peripheral (intermembrane) compartments. These shows that the topology of the mitochondrial inner membrane can have effect on mitochondrial functions by influencing the kinetics of diffusion of metabolites and soluble proteins between the internal compartments defined by this membrane (Mannella et al., 1997).
1.3 Mitochondrial Inner-membrane Dynamics:
Isolated mitochondria has two morphologic states, condensed and orthodox.Condence state is characterized by a contracted, very dense, matrix compartment and wide cristae while orthodox having an expanded, less-dense matrix and more compact cristae(Hackenbrock et al.,1966 ). Changes between these two morphological states has been detected in real time by light scattering or simply by adjusting the osmotic pressure of the external medium, causing water to flow into or out of the matrix. A reversible condensed-to-orthodox transition also occurs during respiration when ADP is in excess amount and fully phosphorylated form (Hackenbrock et al., 1966).
Electron micrograph shows changes in inner mitochondrial membrane as passive unfolding and refolding of the inner membrane. 3D images of rat liver mitochondria obtain by electron tomography indicate that condensed rat liver mitochondria have large pleiomorphic cristae and multiple junctions to each other and to the peripheral region of the inner membrane, that is the region opposed to the outer membrane and the Orthodox rat liver mitochondria have cristae either tubular or flattened lamellae, both types usually having only one junction to the periphery of the inner membrane. For this to occur the inner mitochondrial membranes must undergo fusion and fission, with tubular forms merging into the larger cisternae during matrix condensation. Large lamellar compartment are formed via cristae fusion is strongly suggested by their appearance in tomograms of frozen-hydrated mitochondria (Fig. 2).so that the structural variations that mitochondria undergo in response to osmotic and metabolic changes involve not only the contraction and dilation of the matrix and intracristal space but also by remodeling of the inner mitochondrial membrane. A review of mitochondrial morphologies associated with a variety of osmotic, metabolic, and disease states suggests that inner-membrane topology represents a balance between fusion and fission, with defects (such as crista vesiculation) corresponding to an imbalance in this process (Mannella et al.,2006).
1.4 Inner mitochondrial membrane proteins:
Mitochondrial proteins responsible for maintenance of normal cristae morphology and dynamics are also responsible for mediate inter mitochondrial fusion and organelle division since these processes involve fusion and fission of the inner as well as the outer membranes. For example, the dynamin-like GTPase called Mgm1p in yeast and OPA1 in mammalian cells is required for the fusion of mitochondria. Mutations in this protein cause a progressive, autosomal, dominant retinopathy, dominant optic atrophy (Alexander et al.,2000, Delettre et al.,2002) giving the physiological importance of mitochondrial dynamics. Another protein that directly influences inner-membrane topology is F1F0 ATP synthase. Mutations in subunits e or g of the F0 domain cause lateral dimerization and subsequent oligomerization of these inner membrane complexes and are associated with wrapped cristae lacking tubular junctions (Paumard et al., 2002). This also occurs with the down regulation of the protein mitofilin that regulate interactions of the ATP synthase (John et al., 2005). In ATP synthase dimers, close packing of the bulky extra membrane F1 domains causes the smaller, intramembrane F0 domains , which could induce local bending of the inner membrane.Mgm1/OPA1 has a chaperone-like function for subunit e of the ATP synthase. The loss of the function of Mgm1/OPA1 mutants inhibits ATP synthase dimer formation, which lead to the deficiency of normal tubular crista junctions in these mitochondria.
2 Mitochondrial kinases:
Activated protein kinases can localize to specific cytoplasm sub compartments and mediates many important processes like cell motility (Glading et al., 2001), and signaling endosomes may facilitate communication between neurons(Howe CL et al.,2004). Like hormone- or growth factor-induce signaling cascades, recent advances in redox signaling pathways have very complex function. The mitochondrion is a point of integration for these redox signaling cascades due to its role in cellular metabolism, redox biochemistry, and survival-death decisions. Recent studies have demonstrated that certain components of protein kinase signaling cascades are specifically targeted to mitochondria, where they modulate mitochondrial activity and the release of mitochondrial products that ultimately affect the entire cell.
3 List of Mitochondrial kinases:
- PI3K/Akt/Protein Kinase B(PKB)
- Protein kinase C(PKC)
- JNK/SAPK and p38 MAPK
- Apoptosis signal-regulating kinase 1 (ASK1)
- Glycogen synthase kinase 3β (GSK-3β)
- Protein kinase A (PKA)
- PTEN-induced kinase 1 (PINK1)
(1) PI3K/Akt/Protein Kinase B(PKB)
The protein kinase B (serine/threonine kinase Akt) has a major role in cell proliferation and survival in many cells of the body. Akt is activated by phosphoinositide-dependent kinases to the plasma membrane by products of the type I phosphoinositide 3- kinase (Vanhaesebroeck et al., 2000). Antiapoptotic effects of nitric oxide may be partially mediated by cGMPdependent activation of phosphoinositide 3-kinase and Akt (Ha KS et al., 2003). Inspite of direct effects of Akt in phospho-inactivating the proapoptotic protein BAD (Datta et al., 1997), Akt also activate Raf-1 in the mitochondria (Majewski et al., 1999) and cause expression of proteins involved in the mitochondrial permeability transition pore(Nebigil et al.,2003). Akt can also having role in cell survival through regulation of forkhead transcription factors (Linseman et al., 2005).
In Neuroblastoma and human embryonic kidney cells, insulin-like growth factor 1 Cause rapid translocation of phospho-Akt into mitochondrial subcellular fractions (Bijur et al., 2003). This effect may be cell type specific, as Akt was not observed in mitochondria of mesangial cells stimulated by insulin-like growth factor 1(Kang et al.,2003).
Activated mitochondrial Akt can also phosphorylate β subunit of ATP synthase and of glycogen synthase kinase 3β (GSK3β) (Bijur et al., 2003). GSK3β has been localized by immunoelectron microscopy to the mitochondria, where it functions to phosphorylate and inhibit mitochondrial pyruvate dehydrogenase activity (Hoshi M et al., 1996) and to promote apoptosis (Hetman et al., 2000).
Akt can localize within the mitochondria rather than on its surface most commonly in the mitochondrial membrane fractions and to a lesser degree in the matrix (Bijur et al., 2003). It has pro survival role in mitochondrial membrane permeation. The antioxidant selenite has neuroprotective effects and increases AKT activation by PI3K (Wang et al., 2007). Inhibition of PI3K enhance RGCs survival upon axotomy, in a fashion that depended on the presence of local macrophages PI3K inhibition suppressed the neuroprotective effects of sodium Orthovanadate (Wu et al., 2006).
(2) Protein kinase C (PKC)
The protein kinase C (PKC) family consists of multiple isozymes with distinct distribution patterns in different tissues of the body (Dempsey et al., 2000). Extracellular ligand binds to a receptor tyrosine kinase or G protein-coupled receptor activates phospholipase C and produces inositol triphosphate (IP3) and diacylglycerol (DAG). Calcium released by IP3 causes PKC to bind to membranes, where DAG then activates PKC. Activated PKC phosphorylates many cellular targets, including c-Fos and NF-κB. The isozymes of PKC differ not only in their localization but also in their responsiveness to IP3, DAG, and calcium. There are three subgroups of PKC isoforms, conventional, novel, and atypical, classified on the basis of their responsiveness to these regulators (Parker et al., 2004). The α and β isoforms of PKC were found in a subset of mitochondria in carp retinal Müller cells (Fernandez et al., 1995)
Immunoelectron microscopy studies showed that the kinase was associated with the inner membrane and cristae. Researchers described that PKC isoforms play a direct role in regulating mitochondrial function. Activated PKC isoforms that translocate to the mitochondria are proapoptotic or inhibitory to mitochondrial function. For example, renal proximal tubular cells respond to oxidative stress by activated PKCε to the mitochondria and inhibit the electron transport chain, ATP production, and Na+ transport by direct phosphorylation of Na+-K+-ATPase (Nowak et al., 2004). Treatment of various neoplastic cells with phorbol esters, H2O2, or anticancer agents such as cisplatin and etoposide causes accumulation of PKCδ to the mitochondria, with subsequent releases cytochrome c and induction of apoptosis (Majumder et al., 2000).
In rat cardiac myocytes PKCδ was shown to move to the mitochondria in response to anesthetic exposure or ischemia/reperfusion. PKCδ then activate mitochondrial KATP channels, which then promote cardio protection (Uecker et al., 2003). PKCε also promotes cardioprotection following ischemia/reperfusion through a different mechanism, phosphorylating the voltage dependent anion channel (VDAC) component of the mitochondrial permeability transition pore (Baines et al., 2003). This prevents mitochondrial swelling, outer membrane rupture, release of apoptogenic factors, and decreases in ATP production. PKCε and extracellular signal-regulated kinases (ERKs) interact at the mitochondria to inactivate the proapoptotic protein BAD in cardiac myocytes (Baines et al., 2002). Inactivation of the proapoptotic protein Bax by PKCε in prostate cancer cells renders these cells resistant to androgen-deprivation therapy (McJilton et al., 2003). PKC isoforms translocate from one cell compartment to another, these responses to PKC signaling may be mediated by association with specific anchoring scaffold proteins, RACKs (receptors for activated C kinase) and RICKs (receptors for inactive C kinase) (Mochly-Rosen et al., 1998).
The extracellular signal regulated protein kinases (ERK1/2) has a role in regulating the processes like proliferation, differentiation, adaptation (i.e., cell motility, long term potentiating), survival, and even cell death. ERK has been found in the mitochondria of neurons and non-neuronal cells such as in mouse heart, renal epithelial cells, outer membrane and the intermembrane space of rat brain mitochondria, mouse hippocampus, B65 cells, SH-SY5Y cells; Leydig cells and human alveolar macrophages (Ruben K et al., 2009).The three-tiered ERK signaling involves sequential activation of Raf (MAPKKK), MEK1/2 (MAPKK), and ERK1/2 (MAPK). Depending on its intracellular localization and pathway of activation, Raf-1 can affect apoptosis by different mechanisms (Majewski et al.,1999, Alavi et al., 2003).ERK signaling can have opposite responses to injury even within the same cell type (Chu et al., 2004, Hetman et al., 2004). It has Pro-apoptotic role in mitochondrial membrane permeation. Pharmacological inhibition of ERKs resulted in a reduction of cortical lesion volumes one week after trauma (Mori et al., 2002). Intravenous administration of a specific inhibitor of MEKs after ischemia results in decrease of infarct volume (Namura et al., 2001).
The antiapoptotic protein Bcl-2 plays an important role in targeting Raf-1 to the mitochondria, resulting in phosphorylation of proapoptotic BAD, provides evidence for signaling roles for plasma membrane-targeted versus mitochondrially targeted Raf proteins (Wang et al., 1996). Signaling cascade consisting of Raf-1, MEK1, and the adapter protein Grb10 have been localized to mitochondrial membranes (Nantel et al., 1999). The antiapoptotic effects of mitochondrially localized Raf-1 are independent of ERK activity in myeloid cells (Majewski et al., 1999), and MEK/ERK signaling does mediate antiapoptotic effects of B-Raf in fibroblasts (Erhardt et al., 1999). Phosphorylation of S338 and S339 on Raf-1 promotes mitochondrial translocation and protection of endothelial cells from the intrinsic pathway of apoptosis, whereas Src cause phosphorylation of Y340 and Y341 and MEK/ERK activity are important for protection from death receptor-initiated cell death (Alavi et al., 2003).
ERK can modulate mitochondrial functions and inhibition of MEK, those associated with cell death. For example, ERK signaling promotes mitochondrial ATP synthase function in glucose-deprived astrocytes (Yung et al., 2004), to maintain mitochondrial membrane potential and prevent cytochrome c release (Lee et al., 2004), and to inactivate the proapoptotic protein BAD (Jin et al., 2002). ERK has also role in promoting oxidative neuronal injuries (Chu et al., 2004) and in neurodegenerative diseases (Tobiume et al.,2002, Kulich et al.,2001) MEK/ERK promotes organophosphate induce mitochondrial vacuolation(Isobe et al., 2003), apoptotic translocation of Bax to the mitochondria(Isobe et al., 2003), and nonapoptotic programmed cell death(Sperandio et al., 2004). As pro- and antiapoptotic effects of MEK/ ERK signaling could be mediated by downstream targets or at the transcriptional level (Bonni et al., 1999), these studies do not necessarily indicate mitochondrial targeting of ERK.
Mitochondrial targeting of ERK signaling was first derived from biochemical subcellular fractionation studies. In renal tubular cells, both activated ERK1/2 and PKCα are enriched in mitochondrial fractions during cisplatin injury, where they increase mitochondrial membrane potential, decrease oxidative phosphorylation, and increase caspase-3 activation and apoptosis (Nowak et al., 2002).ERK activity in phosphorylating both Bcl-2(Deng et al., 2000) and BAD (Kang et al., 2003) are associated with increased levels of activated ERK colocalizing or co-immunoprecipitating with the Bcl-2 family members in mitochondria.
Immuno-electron microscopy studies shows presence of phosphorylated ERK1/2 within the mitochondrion (Zhu et al., 2003, Alonso et al., 2004). Phospho-ERK was found at high labeling densities within a subset of mitochondria in degenerating neurons from patients of Parkinson's disease and Lewy body dementia (Chu et al., 2003) and distinct granular cytoplasmic pattern of staining are not observed in control patients(Zhu et al., 2002).
(4) JNK/SAPK and p38 MAPK
The p38 MAPKs and the JNK (c-Jun N-terminal kinase) / SAPK (stress-activated protein kinase) are of MAPK family membranes and involved in prodeath signaling (Matsuzawa et al., 2001). The p38 and JNK are activated by a MAP kinase (MKK), which is activated by a MAPKKK in response to a stimulus like oxidative stress, irradiation, or proinflammatory cytokines such as tumor necrosis factor α.
Role of p38 MAPK signaling in cell death includes translocation of proapoptotic Bax from cytosolic to mitochondrial compartments (Park et al., 2003 Shou et al., 2003), caspase-independent potassium efflux (Bossy-Wetzel et al., 2004), and transcriptional regulation of TR3, a steroid receptor-like protein that translocates from the nucleus to the mitochondria to initiate the intrinsic apoptotic pathway (Bossy-Wetzel et al., 2004). Irradiation causes translocation of both p38 and JNK1 to mitochondrial subcellular fractions (Epperly et al., 2002). The effects of JNK on the mitochondria involve stimulation of apoptosis. Treatment of isolated rat brain mitochondria with active JNK causes the inhibition of antiapoptotic Bcl-2 and Bcl-xL and release of cytochrome c (Schroeder et al., 2003).
The mitochondrial JNK is activated by oxidative stress in cardiac myocytes, and cause the release of cytochrome c lead to apoptosis (Aoki et al., 2002). Treatment with phorbol esters cause localization of JNK to the mitochondria in human U-937 leukemia cells, where it binds to and inhibits Bcl-xL, promoting apoptosis (Kharbanda et al., 2000, Ito et al., 2001). Mitochondrial JNK can also cause the release of Smac, the activator of caspase that promotes caspase-9 activity (Chauhan et al., 2003).
JNK also phosphorylates and oligomerize proapoptotic BAD (Bhakar et al., 2003). JNK signaling can yield cell survival under some conditions. JNK can inactivate the pro-apoptotic protein BAD (Yu C et al., 2004). Activated JNK phosphorylates Bcl-2 at Ser70 in the mitochondrial membranes of interleukin-3-dependent hematopoietic cells. This occurs under conditions of stress or by exposure to interleukin-3, resulting in enhanced antiapoptotic activity of Bcl-2(Deng et al., 2001). It has Pro-apoptotic role in mitochondrial membrane permeation. JNK3 (but not JNK1 nor JNK2) absence conferred significant neuroprotection to axotomized neurons. The absence of JNK3 (but not of JNK1 nor of JNK2) resulted in a substantial resistance against kainate-induced seizures, which correlated with improved survival (Brecht et al., 2005). Pharmacological JNK inhibitors diminished several manifestations of apoptosis and reduced infarct volume (Gao et al., 2005). Intravitreal administration of a p38MAPK inhibitor induced apoptosis (Kikuchi et al., 2000). Oral administration of a p38MAPK inhibitor during pre- and post-ischemia provided dose-dependent neuroprotective effects (Legos et al., 2001). Pharmacological inhibition of p38MAPK protects neurons from NO-mediated degeneration (Xu et al., 2006).
(5) Apoptosis signal-regulating kinase 1 (ASK1)
All living systems are exposed to numerous physicochemical stressors, and appropriate responses to these stresses at the cellular level are essential for the maintenance of homeostasis. The mitogen-activated protein Kinase (MAPK) cascades are having major signaling pathways in regulation of these cellular stress responses (Kazuki et al., 2009). The MAPK pathway consists of a cascade of three protein kinases. These protein kinases are sequentially activated, such as the MAPK kinase kinase (MAPKKK) phosphorylates and activates the MAPK kinase (MAPKK), which then phosphorylates and activates the MAPK.
MAPKs have a wide variety of cellular functions, including proliferation, differentiation, migration and apoptosis. ASK1 identified as a member of the MAPKKK family and activate the MAPKK 4 (MKK4) - JNK and MKK3/6-p38 pathways but not the MAP/ERK kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway (Ichijo et al., 1997). Tumor necrosis factor-α receptor-associated factors (TRAFs) having important role in the regulation of ASK1 activity. In TRAF family proteins, TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6 are associate with ASK1, but only TRAF2, TRAF5 and TRAF6 increase ASK1 kinase activity (Nishitoh et al., 1998). TNF-α treatment induces JNK activation in a TRAF2- dependent manner (Yeh et al., 1997, Tobiume et al., 2001). Phosphorylation of Thr845 in mouse ASK1 have role in activation of ASK1 (Tobiume et al., 2002).
Endoplasmic reticulum (ER) stress activates ASK1 and involved in variety of neurodegenerative diseases (Lindholm et al., 2006). It has Pro-apoptotic role in mitochondrial membrane permeation. Decreased activation of ASK1/JNK by the antioxidant selenite correlated with neuroprotective effects (Wang et al., 2007).
(6) Glycogen synthase kinase 3β (GSK-3β)
Glycogen synthase kinase-3β (GSK-3β) is a constitutively active 47-kDa Ser/Thr protein kinase. It has about 40 substrates and having functions like cell proliferation, growth and death. GSK-3ß has a significant role in the regulation of apoptosis. Apoptotic injury is increased by the over-expression of GSK-3ß lead to cellular injury. During oxidative stress, GSK-3ß can lead to the activation of caspase 3 and cytochrome c release ultimately lead to apoptosis. Mechanism of GSK-3β is phosphorylation at Ser and Tyr residues, complex formation with scaffold proteins, priming of substrates and intracellular translocation. GSK-3β has been involved in serious diseases such as Alzheimer's disease, bipolar mood disorder, cancer and ischemia/reperfusion injury (Tetsuji et al., 2009). It has Pro-apoptotic role in mitochondrial membrane permeation. Clinical dose of lithium inhibits GSK-3β resulted in significant axon sprouting and functional recovery (Dill et al., 2008).
(7) Protein kinase A (PKA)
The protein kinase A (PKA) signaling pathway involves responses to hormonal stimulation which are often cell type specific.The PKA pathway involves the binding of an extracellular molecule to a G protein-coupled receptor, which catalyzes the formation of intracellular cyclic AMP through the activation of adenylate cyclase.Cyclic AMP then binds to the two regulatory subunits of PKA, thereby releasing the two catalytic subunits to phosphorylate serine and threonine residues on target proteins.
These subunits enter the nucleus and phosphorylate transcription factors such as CREB and NF-κB. PKA signaling in specific subcellular compartments has been recognized with the discovery of specific anchoring scaffold proteins. PKA activity has been identified within the mitochondria in a wide variety of species, including human (Kleitke et al., 1976).
Mitochondrial targeted PKA activities have positive effects on the mitochondria. PKA localized to the inner membrane and matrix of mitochondria phosphorylates and promotes the activity of complex I (NADH dehydrogenase) (Technikova-Dobrova et al., 2001).
AKAP (A-kinase anchoring proteins)-mediate the activation of PKA to the cytoplasmic surface of mitochondria results in phospho-inhibition of the proapoptotic protein BAD, enhancing cell survival (Harada et al., 1999, Affaitati et al., 2003). A peripheral benzodiazepine receptor-associated protein functions as an AKAP that promotes mitochondrial steroid genesis (Liu et al., 2003).
AKAP-121 can also function as targeting of Mn-superoxide dismutase mRNA to the mitochondria for localized translation of this important antioxidant (Ginsberg et al., 2003).The small G-protein Rab32, which regulates mitochondrial fission, appears to function as a mitochondrially targeted AKAP(Alto et al., 2002). Thus, mitochondrial targeting of PKA appears to be involved in regulating most major mitochondrial functions, promoting respiration, antagonizing cell death, and regulating mitochondrial protein expression and biogenesis.
(8) PTEN-induced kinase 1 (PINK1)
PINK1 is a serine/threonine kinase having similarity to calcium/calmodulin regulated kinases. The primary sequence for PINK1 includes a canonical N-terminal mitochondrial leader sequence (Ruben K et al., 2009). PINK1 has been found in the mitochondria human brain and it is cleaved by matrix proteases. Transmembrane domain of PINK1 is responsible for its insertion in to outer mitochondrial membrane. The C-terminal domain of PINK1 having role of its auto phosphorylation (Liu et al., 2008). Point mutations and truncations of PINK 1 have been mapped throughout the transmembrane, kinase and C-terminal domains lead to impaired kinase activity and promote degradation, or induce misfolding of PINK1. The TNF receptor associated protein 1 (TRAP1, or Hsp75) are substrate for PINK1, and the serine protease Omi/Htra2 and heat shock proteins, Hsp90/Cdc37 are PINK1 binding proteins. So degradation of PINK1 catalytic activity leads to disease like parkinsonian neurodegeneration (DeFeo et al., 1981).
4 Human Diseases associated with Mitochondrial Kinases
Mitochondria are important because of the Respiratory chain which is the major sites of energy production in all cells (Taylor et al., 2005). Mitochondria perform many functions in different tissues and cells so there are so many different mitochondrial diseases associated with different tissues of the body. Each disease produces abnormalities that are difficult to diagnose. There are complex relationship between the genes and cells that are responsible for maintaining our metabolic processes running smoothly; it is a basis of mitochondrial diseases. Mitochondrial diseases is due to degeneration of the mitochondria in specialized compartments present in every cell of the body except RBC (red blood cells).When mitochondria fail to generate energy, less energy is generated in the cell so cell injury and even cell death can occur. If this is repeated throughout the whole body, whole systems begin to fail, and the life of the person is severely compromised. The disease affects more in children as compared to adult but onset is becoming more and more common. Mitochondria diseases causes damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.
Kinases that are associated with mitochondria during neuronal injury include mitogen activated protein kinases (MAPK) such as extracellular signal regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK), protein kinase B/Akt, and PTEN-induced kinase 1 (PINK1). Their sites of action within mitochondria and specific kinase targets are still unclear but these signaling pathways regulate mitochondrial respiration, transport, fission-fusion, calcium buffering, reactive oxygen species (ROS) production, mitochondrial autophagy and apoptotic cell death( Kachergus et al., 2005).
5 List of mitochondrial kinases associated human diseases:
A) Neurodegenerative diseases:
1 Parkinson's disease (PD)
Parkinson's disease is a debilitating, movement disorder that affects around 1 million people in North America.
Symptoms: Motor symptoms can be due to degeneration of endogenously pigmented midbrain neurons of the nigrostriatal projection. Olfactory, autonomic and cognitive dysfunction. Most of the cases have no known cause; oxidative stress, disordered protein handling/degradation, and mitochondrial dysfunction are mechanistically observed factors in sporadic PD due to toxin/pesticide exposures, and in models of familial PD (Ruben et al., 2009).
Factors like Disturbances in mitochondrial function, transport, dynamics and turnover have central role in neurotoxin, environmental and genetic approaches to Parkinson's disease (Ruben et al., 2009). In addition to changes in mitochondrial fission/fusion machinery and trafficking, autophagic degradation process has a critical role in regulating mitochondrial quality and content (Kiselyov et al., 2007). Macroautophagy has a role in membranous engulfment of cytoplasmic cargo bodies for lysosomal degradation, and this the major degradative pathway for organelles and insoluble proteins. There is deregulation of macroautophagy and of chaperone-mediated autophagy observed in toxin and genetic models of PD (Ruben et al., 2009).
Gene multiplication and α-synuclein mutations are autosomal dominant of PD in model of parkinsonian neurodegeneration (Polymeropoulos et al., 1997). Aggregation of α-Synuclein, Lewy bodie formation and mutation in leucine rich repeat kinase 2 (LRRK2) are found in the sporadic and dominant forms of PD (Kachergus et al., 2005). Parkin, ATP13A2, DJ1 and PTEN induced kinase 1(PINK 1) are involved in autosomal recessive Parkinsonism disease. PINK1 and Parkin regulates mitochondrial morphology and turnover (Ruben et al., 2009).
In human PD brain and diffuse Lewy body diseases, Phospho-ERK (p-ERK) in the cytoplasm and mitochondria of midbrain dopaminergic neurons are increased. The punctuate staining of mitochondrial p-ERK in PD is distinct from the diffuse staining pattern observed after cerebral ischemia. P-ERK is not elevated in substantia nigra indicates that this type of dysregulated ERK1/2 signaling may be relatively specific to PD (Ruben et al., 2009). MPTP/MPP, 6-OHDA, rotenone, and toxic dose of dopamine cause injury to dopaminergic cell lead to alteration in ERK activity (Chu et al., 2004, Chuenkova et al., 2003). Mitochondrial ERK cause autophagy/mitophagy even in the absence of toxin injury it could act as a sensor of mitochondrial injury induced by toxins. In 6-OHDA model and a dopamine toxicity model, a small amount of p-ERK1/2 activated during injury and translocate to the nucleus while majority amount found in the cytoplasm and mitochondria. This process lead to excessive mitophagy harmful in the neuronal cells (Ruben et al., 2009). Mutations in the leucine-rich repeat kinase 2 genes (LRRK2) can also cause late-onset Parkinson's disease.LRRK2 has Ras/GTPase-like, a protein kinase domain, leucine rich domain, and WD40 domains, all has a major role in signaling(Kachergus et al., 2005). The kinase domain has a catalytic core component common to tyrosine and serine/threonine kinases, and is a homologous to mitogen activated protein kinase kinase kinases (MAPKKK) (Biskup et al., 2006).
JNK has a major signaling role in PD pathogenesis.JNK activity has been increased in MPTP animal models, MPP+ cell culture model, rotenone neurotoxicity and the 6-OHDA model(Ruben et al., 2009). Activation of JNK lead to neuronal cell death and downstream targets include cyclooxygenase 2 and the p53 protein. JNK activation leads to its translocation to mitochondria and promote mitochondrial dysfunction ultimately to degeneration in PD. Parkin is an E3 ubiquitin ligase, encoded by Parkin gene and in parkinsonism this gene has been found to be most commonly mutated. Parkin has protective role in dopaminergic neurons against multiple PD-related toxicities.
Knockdown of DJ-1 in Drosophila lead to mitochondrial dysfunction and decrease in the Akt activity. In Oxidative stress condition there is aggregation of a-synuclein which affects Akt activity in neurons. Due to increase in b-synuclein antagonize the toxic and aggregating effects of a-synuclein.Overexpression of PINK1 has protective effect against a variety of toxic substances like staurosporine, rotenone, proteasome inhibition MPP+ and 6-OHDA.Mutation in the PINK 1 is also one of the cause of PD because of loss of kinase activity, protein stability and protein misfolding (Ruben et al., 2009).
2. Alzheimer's disease
Mitochondrial dysfunction is one of the most common causes of Alzheimer disease (AD). While the mechanisms of mitochondrial dysfunction in AD and how mitochondrial dysfunction leads to Alzheimer pathogenesis remains unclear, recent studies shows that abnormal mitochondrial dynamics likely play a key role in AD pathogenesis(Xinglong et al., 2009).
In Alzheimer's disease, GSK-3ß expression has been found in the cytoplasm of pretangle neurons cause development of neurofibrillary changes. GSK-3ß can be activated by Aß exposure in cultured hippocampus neurons.GSK-3ß can have role in regulation of amyloid precursor protein (APP) processing and phosphorylation of tau. GSK-3ß can release Aß by increasing activity of APP. Hyperphosphorylated tau protein can form neurofibrillary tangles that contain paired helical filaments.
GSK-3ß can phosphorylate tau at sites required for the formation of paired-helical-filaments (Z.Z. Chong et al., 2005). There is also Point mutation in the presenilin-1 (PS1) gene lead to tau phosphorylation and GSK-3ß activity and it is one of the causes of Alzheimer's disease.
The first oncogene found was the Ras genes encoded by rat sarcoma virus, v-H-Ras and v-K-Ras (DeFeo et al., 1981). Mutated form of this Ras gene has been bound with GTP and become active. Human neoplasms contain this mutated form of Ras gene with about 30% of all cancers containing Ras mutation (Mor et al., 2006). Apart from Ras mutation other kinases like B-Raf mutation, V600E from MAPK pathway has been associated with cancer development. Mutation in V600E lead to formation of highly active form of B-Raf kinase so the Raf/MEK/ERK pathway is in hyperactive state causes Increased ERK phosphorylation and expression has been found in pancreatic cancer and prostate cancer (X. Tan et al., 2004). Colon carcinoma is due to increased phosphoryalation of MEK activity (S.H. Lee et al., 2004). Increased activity of MAPK pathway has been observed in breast cancer (V.S. Sivaraman et al., 1997). Proteins that alter the sub cellular localization of ERK1/2 have role in cancer disease. Expression of Mxi2, a p38MAPKsplice form, increases the concentration of ERK1/2 in the nucleus and over expression of Mxi2 has been found in certain renal cancers (B. Casar et al., 2006). PI3K-PTEN-PKB/Akt signaling pathway is activated in many tumors due to mutations in PI3K or PTEN, or amplification/overexpression/mutation of PKB isoforms (Valeria G et al., 2009).
Mutation in the pleckstrin homology domain of AKT1 at nucleotide position 49, G>A transition results in a lysine substitution for glutamic acid at amino acid 17 [AKT1(E17K)] that results in a mutant Akt1 protein with increased plasma membrane recruitment has been described in breast, colorectal and ovarian clinical cancer specimens(F.E. Bleeker et al., 2009). Both direct mutation in Akt and also indirect changes in modifiers of Akt activity increase pathway strength and have role in inherited and somatic tumors in humans (J. Brugge et al., 2007).
Alteration of PKCδ activity has been proposed as a mechanism of carcinogenesis.overexpression and transcolation of PKCδ to mitochondria were observed in normal and neoplastic keratinocytes undergoing apoptosis (Valeria G et al., 2009).
6 Kinases as drug targets for the treatment of diseases:
Decrease in the kinase activity has a major role in cancer cells proliferation. Accordingly, inhibition of the tyrosine kinase activity of the oncogenic BCR (breakpoint cluster region)-ABL1 fusion Protein, which is a causative transforming event in chronic myeloid leukemia (CML) (G.Q. Van et al., 1990).
A number of agents, such as the tyrosine kinase inhibitor, Imatinib, which inhibits the ABL, KIT and PDGFR kinases, have been developed to inhibit receptor function (C.H. Pui et al., 2007). Intracellular components of the MAPK cascade, farnesyl transferase inhibitors (FTIs) have positive responses for breast, pancreatic and colorectal cancers as well as in leukaemia. These compounds compete with farnesyl transferases for the CAAX motif, preventing the addition of a farnesyl group. FTIs having some success in treating hematologic cancers, their use as Ras inhibitors has been complicated by the fact that K-Ras and N-Ras undergo alternative prenylation by a related enzyme, geranylgeranyltransferase I (GGTaseI), when FTase activity is inhibited by FTIs. Hence, FTIs are not effective inhibitors of Ras function.
The multi-kinase inhibitor, sorafenib, which targets B-Raf, C-Raf, VEGFR and PDGFR, has been approved by the US FDA in 2005 for the treatment of advanced renal cell carcinomain adults. Two MEK inhibitors, PD0325901 and AZD6244, decrease in vitro proliferation, soft-agar colony formation and matrigel invasion of melanoma cell lines with the V600EB-Raf mutation (E.A. Collisson et al., 2003).
Two well-known and isoform of PI3K inhibitors are the fungal metabolite wortmannin and LY294002. Wortmannin is an irreversible inhibitor that forms a covalent bond with a conserved lysine residue involved in the phosphate-binding reaction, whereas LY294002 is a classical reversible, ATP competitive PI3K modulator (Valeria G et al., 2009).
Midostaurin (also known as PKC412 or nbenzoylstaurosporine), similar to UCN01 (7-hydroxystaurosporine), exhibits improved selectivity for PKC ATP-binding sites, but shows modest isozyme specificity. nPKCs and cPKCs, midostaurin inhibits other tyrosine kinase pathways, including VEGFR2, fms-related tyrosine kinase 3, platelet-derived growth factor receptor and KIT kinases.
Table 1: kinase inhibitor used in cancer therapeutics
NSCLC, breast, colon, pancreatic
NSCLC, colon, prostate, myeloma
nPKC and cPKC
Human body can receive, process, and transmit information from external signals, such as hormones, drugs, or even light. Signal transduction is a process in which receptors on the cell surface receive information from outside of the cell and transmit this information to an amplifier or effectors. Mitochondria has major role in apoptosis signaling pathways. Mitochondria are not exclusively ATP suppliers but take part in regulatory and signaling events, responding to multiple physiological inputs and regulating cell proliferation and death. The data indicate that mitochondria integrate a three compartment cycle that allows MAPKs and Akt to be post translationally oxidized and controls its degree of phosphorylation and in consequence their subcellular movements. These effects activate cell proliferation through regulation of genes and mitochondrial components while H2O2 accumulation gradually favors the transition from growth to quiescence. The mitochondrial kinase activation opens new fields in the balance between cell proliferation and apoptosis. And disruption between these two mechanism lead to tumorgenesis, the understanding of this mechanism suggests new preventive and therapeutic measures in the treatment of cancer, still the most important cause of death in the whole world.
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