Types of Mitochondrial Diseases

Types of Mitochondrial DiseasesAbstractMitochondrion is the primary site of zip fastener and adenosine triphosphate generation so it is call(a)ed power contribute of the booth. Mitochondria argon composed of two different types of tissue layers like an outer tissue layer, an inner tissue layer and a protein-rich matrix. Protein kinases can localize to specific cytoplasmic sub compartments and mediates many another(prenominal) classical transites like cell motility and many sign of the zodiac eventidets. The mitochondrion is a point of integration for these signaling descend 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 3 (GSK-3),Protein kinase A (PKA),PTEN-induced kinase 1 (PINK1) atomic number 18 associated with mitochondria and modulate mitochondrial attain mechanism and the rel ease of mitochondrial products affects mitochondrial respiratory chain, transport, fission- union events, calcium turnover, oxidizable oxygen species (ROS) merchandise, mitochondrial autophagy and apoptotic cell death. Mitochondrial diseases ar due to devolvement of the mitochondria in specialized compartments present in e very cell of the body. Mitochondria diseases wee-wees damage to cells of the brain, heart, liver, pointless muscles, kidney and the endocrine and respiratory systems. So this surveil focuse on various kinases associated with mitochondria, their role in progression of neurodegenerative diseases and treatment.Introduction1 MitochondriaMitochondrion is present in every eukaryotic cell having size range of 0.5 to 10 m 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 ar composed of two different types of membranes like an outer membrane, an inner membrane and a protein-ric h 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 baffle, 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 re theoretical accounting of the inner membrane in the case of caspase-mediated cell death and cytochrome c release (Scorrano et al., 2002) and mitochondrial fragmentation (Sun et al., 2007). Cell controls the mitochondrial structure, its function and reception against various stimuli (Mannella et al., 2 006)1.1 StructureA 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 distance ( 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 membraneThe inner membrane contains invaginations called cristae. The cristae are not random folds but these are small regions that open through narrow tube-shaped 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 tubelike cristae junctions is 10-15 nm (Fig. 2).This is enough to pass metabolites and many soluble proteins and the inner membrane restrict inseparable diffusion rates. For exa mple, 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, conduct 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 postulate 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 dynamics of diffusion of metabolites and soluble proteins between the internal compartments defined by this membrane (Mannella et al. , 1997).1.3 Mitochondrial Inner-membrane DynamicsIsolated 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(prenominal)-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 two-sided 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 still 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 duple junct ions 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 reply 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 t opology represents a balance between fusion and fission, with defects (such(prenominal) as crista vesiculation) corresponding to an imbalance in this process (Mannella et al.,2006).1.4 Inner mitochondrial membrane proteinsMitochondrial proteins responsible for aid 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 subse quent 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 trigger off 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- o r increase factor-induce signaling cascades, recent advances in redox signaling tracts 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 natural process and the release of mitochondrial products that ultimately affect the entire cell.3 List of Mitochondrial kinasesPI3K/Akt/Protein Kinase B(PKB)Protein kinase C(PKC)Raf-MEK-ERKJNK/SAPK and p38 MAPKApoptosis signal-regulating kinase 1 (ASK1)Glycogen synthase kinase 3 (GSK-3)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 study 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 nitrous oxide may be partially mediated by cGMPdependent energizing 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 case of proteins voluminous 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 gentleman 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 spy in mitochondria of mesangial cells stimulated by insulin-like g rowth factor 1(Kang et al.,2003).Activated mitochondrial Akt can also phosphorylate subunit of ATP synthase and of glycogen synthase kinase 3 (GSK3) (Bijur et al., 2003). GSK3 has been localized by immunoelectron microscopy to the mitochondria, where it functions to phosphorylate and inhibit mitochondrial pyruvate dehydrogenase suppleness (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-B. 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 advertisement on the grounding of their responsiveness to these regulators (Parker et al., 2004). The and isoforms of PKC were found in a subset of mitochondria in carp retinal Mller cells (Fernandez et al., 1995)Immunoelectron microscopy studies showed that the kinase w as 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, nephritic proximal tubular cells respond to oxidative mark by activated PKC 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 PKC to the mitochondria, with subsequent releases cytochrome c and induction of apoptosis (Majumder et al., 2000).In rat cardiac myocytes PKC was shown to move to the mitochondria in response to anaesthetic(a) exposure or ischemia/reperfusion. PKC then activate mitochondrial KATP channels, which then promote cardio tax shelter (Uecker et al., 2003). PKC also promotes cardioprotection following ischemia/reperfusion through a different mechanism, phosphorylating the electric potential dependent anion channel (VDAC) component of the mitochondrial permeability transition pore (Baines et al., 2003). This retains mitochondrial swelling, outer membrane rupture, release of apoptogenic factors, and decreases in ATP production. PKC and extracellular signal-regulated kinases (ERKs) interact at the mitochondria to demob the proapoptotic protein BAD in cardiac myocytes (Baines et al., 2002). Inactivation of the proapoptotic protein Bax by PKC 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).(3) ERK-Raf-MEKThe 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 gentle 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 mitochondria l membrane permeation. Pharmacological inhibition of ERKs resulted in a reduction of cortical lesion volumes one calendar 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 R af-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 nonapoptoti c 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 fractional process studies. In renal tubular cells, both activated ERK1/2 and PKC 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 (Z hu 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 Parkinsons 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 MAPKThe 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 .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 transcriptiona l 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 being 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 pr omotes 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(prenominal) 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- 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- 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 mi tochondrial membrane permeation. Decreased activation of ASK1/JNK by the antioxidant selenite correlated with neuroprotective effects (Wang et al., 2007).(6) Glycogen synthase kinase 3 (GSK-3)Glycogen synthase kinase-3 (GSK-3) 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-3 has a significant role in the regulation of apoptosis. Apoptotic injury is increased by the over-expression of GSK-3 lead to cellular injury. During oxidative stress, GSK-3 can lead to the activation of caspase 3 and cytochrome c release ultimately lead to apoptosis. Mechanism of GSK-3 is phosphorylation at Ser and Tyr residues, complex formation with scaffold proteins, set of substrates and intracellular translocation. GSK-3 has been involved in serious diseases such as Alzheimers disease, bipolar mood disorder, cancer and ischemia/reperfusion injury (Tetsuji et al., 2009). It has Pro-apoptotic role in mit ochondrial membrane permeation. clinical dose of lithium inhibits GSK-3 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-B. 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, includ ing 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, mitochondr ial 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) ar e 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 KinasesMitochondria 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. apiece 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 b lood 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 go 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 spec ies (ROS) production, mitochondrial autophagy and apoptotic cell death( Kachergus et al., 2005).5 List of mitochondrial kinases associated human diseasesA) Neurodegenerative diseasesParkinsons disease Alzheimers diseaseB) Cancer1 Parkinsons disease (PD)Parkinsons disease is a debilitating, movement disorder that affects around 1 million people in mating 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, disquiet 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 Parkinsons disease (Ruben et al., 20 09). 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 -synuclein mutations are autosomal dominant of PD in model of parkinsonian neurodegeneration (Polymeropoulos et al., 1997). Aggregation of -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 regula tes 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 midbr