Mitochondrial ATP Synthase as a Molecular Machine

4871 words (19 pages) Full Dissertation in Full Dissertations

06/06/19 Full Dissertations Reference this

Disclaimer: This work has been submitted by a student. This is not an example of the work produced by our Dissertation Writing Service. You can view samples of our professional work here.

Any opinions, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of UK Essays.

Abstract

A molecular machine is defined as “an assembly of distinct number of molecular components that are designed to perform machinelike movements (output) as a result of an appropriate external stimulation (input) [1].” Mitochondrial ATP synthase is a molecular machine naturally present in cells [1]. It is a multisubunit protein complex that uses the free energy derived from an electrochemical [H+] gradient to produce adenosine triphosphate (ATP) [2]. The proton gradient is generated by the electron transport chain (ETC) and the ATP machine tightly associated with the transport chain is also referred to as Complex V of ETC [2]. The energy stored in ATP is the source of fuel for most of the cellular processes [3]. The ATP synthase present in the mitochondria exists as a dimer that provides stability to the multisubunit complex and facilitates its function of ATP synthesis [2]. This review focuses on details of the multi-subunit complex, its characteristics, and machine-like movements.

 

Molecular Components and Organization

Mitochondrial ATP synthase consists of two principal domains: F0 domain in the inner mitochondrial membrane region and F1 domain in the matrix [2]. The membrane spanning, asymmetric F0 domain consists of a ‘c-ring,’ subunits a, b, e, f, g, and A6L. The ‘c-ring’ consists of eight ‘c-subunits,’ the sequences of which are identical in vertebrates, but highly conserved among invertebrates [4]. The c-subunits comprise of 9-12 twin -helices assembled in the membrane as a spanning array and interact with ‘a-subunit’ as well as the central stalk in the F1domain [1]. The ‘a-Subunit’ has 5-7 transmembrane -helices, two half channels to facilitate proton flow into the c-subunit [2] [1]. There are additional subunits that span the membrane such as e, f, g, and A6L within the FO-domain [2]. In addition to the c-ring and ‘a-subunit’ in the F0 domain, there is a ‘b-subunit’ in association with ‘a-subunit.’ It has one copy of ‘d’ and ‘F6’ subunits and oligomycin sensitivity conferral protein (OSCP). The OSCP, b, d and F6 subunits, lie on one side of the machine and represent the peripheral stalk [2]. There is a proton channel at the interface of ‘a-subunit’ and ‘c-subunit,’ through which the protons flow to the F1 domain.

The F1 domain consists of five protein subunits alpha (), beta (), gamma (), delta () and epsilon () having a stoichiometry of 3:3:1:1:1 respectively [1] [5]. The subunits , , and  represent the central stalk of the synthase complex [2] and the terminal region of -subunit forms a coiled-coil and penetrates the core of 3-3 hexamer ring [6]. The -subunits have three catalytic sites, and each site has a distinct conformation[1]. Overall, the c-ring and the components of the central stalk form the rotors whereas, the ‘a-subunit,’ along with the accessory subunits – e, f, g and A6L and the peripheral stalk form the stators [6].

Mechanism and Output

The primary function of the mitochondrial ATP synthase is to synthesize ATP by phosphorylating adenosine diphosphate (ADP) in the F1 domain [2]. The energy required for synthesizing ATP is derived from a proton [H+] gradient that exists between the intermembrane space (IMS) and the matrix. This gradient establishes a proton motive force [2], allowing the translocation of protons across the mitochondrial membrane. The proton flow is mediated by the close association of ‘c-subunit’ with ‘a-subunit’ [3]. Each ‘c-subunit’ in the C-ring has a charged residue that is Glutamate 59 (E59) in the middle of the lipid bilayer, that interacts with Arginine 159 (R159)in ‘subunit-a’ [3]. The protons flowing through the half channel in ‘subunit-a’ will sequentially protonate and deprotonate E59 in the ‘c-subunits’ allowing the protons to flow into the matrix. The mechanism begins with the flow of [H+] through the half channel of ‘subunit-a.’ These protons bind to ‘c-E59’ and disrupt its electrostatic interaction with ‘a-R159′. The disruption of interaction results in the neighboring ‘c-E59’ releasing its proton into the matrix through the other half channel. The deprotonated ‘c-E59’ then binds to ‘a-R159’ resulting in a one-step turn of the ring [3].  Thus, the proton translocation facilitates the rotation of the ‘c-ring.’ Since the ‘c-ring’ is extensively interacting with the -shaft, the c-ring rotation, causes the central stalk (, , and ) to rotate along with it [4, 6].

The -subunit is asymmetric and inflicts different conformations such as ‘open,’ ‘loose’ and ‘tight’ states in the catalytic sites of -subunits [4]. The open form has no nucleotide and is termed ‘E’ site, the loose form has bound ADP and Pi and is termed  ‘DP’site. The tight form has one bound ATP and is termed ‘TP’ site [6]. As the -shaft rotates, it pauses at 120 due to the asymmetry [7]. This 120 rotation results in each site, switching its conformation, such that the tight form that had bound ATP is now in its open form(TP-E), causing the release of ATP. The loose form that had bound ADP and Pi is now in the tight form resulting in the synthesis of ATP (DP-TP) and the open form is now in the loose form (E-DP), where 1 ADP and Pi comes and binds to it. ‘DP’ does not synthesize ATP because the ADP and Pi are not as close together, as they are in the tight form. Overall, the -shaft rotates in a clockwise direction synthesizing and releasing 1 ATP for every 120 rotation, changing the conformations of -subunits from E to DP to TP [6]. Thus, for one complete rotation of the c-ring (8 c-subunits), 8[H+] cross the inner membrane, resulting in a 360 rotation of the -shaft synthesizing 3 ATP molecules. Thus, the bioenergetics cost is 2.7 [H+]/ATP [4, 8].

ATP synthase is a reversible complex and therefore can pump protons back into the intermembrane space when [H+] concentrations are low, by hydrolyzing ATP [7]. In this case, the -subunit in complex with  and  rotates counter-clockwise and depending on the direction of this rotation, the conformations in the -subunit change from TP to DP to E conformation. The energy from ATP hydrolysis facilitates the pumping of protons back into the inter membrane space through the counter-clockwise rotation of the c-ring [6].

Overall, the ATP synthase complex functions as a machine, where the central stalk couples the reaction in the FO and F1 domains. The protons flow from F0 region, rotates the -shaft, causing conformational changes in the -subunits of F1, resulting in ATP synthesis. Conversely, it hydrolyzes ATP in the F1 domain, reversing the shaft rotation and pumping protons from F0 region back to the IMS [7].

Energy Input

As mentioned earlier, ATP is synthesized using free energy derived from the electrochemical gradient of protons. This gradient establishes a proton motive force [9]. The proton motive force has two components: a pH gradient (pH) due to the differences in concentration of [H+] in the intermembrane space and the matrix and a membrane potential (), due to a charge being present on the protons [2, 9]. A proton gradient is generated during respiration, by the electron transport chain(ETC) present in the inner membrane. The ETC pumps protons from the matrix while transporting electrons from NADH and FADH2 to reduce O2 to H20 [10]. These protons are pumped into the intermembrane space resulting in the mitochondrial matrix having less [H+] concentration compared to the IMS generating a pH gradient. However, there is always a balance of positive and negative ions on both sides of membrane and pH does not affect the voltage potential of the membrane, due to which the  is considered the primary driving force of ATP synthesis [9] [11]. The total free energy generated from electron transport chain in the form of   is about -220kJ/mol [12] and the free energy required to synthesize 1 ATP from ADP and Pi is +31.3kJ/mol [13]. Thus, oxidation of 1 molecule of NADH provides sufficient energy to synthesize several molecules of ATP. Since, the oxidation of NADH leads to the phosphorylation of ADP, this process is known as Oxidative Phosphorylation(OXPHOS) [2].

ATP Synthasome

One of the characteristic features of mitochondrial ATP synthase is the presence of ATP Synthasome. The ATP synthase in complex with two motors, an adenine nucleotide carrier (ANC), also called as an ADP/ATP translocase (ANT) [14] and an inorganic phosphate carrier (PIC) is known as ATP Synthasome [14] [15]. The ATP synthase complex is dependent on these two carriers to bring in the substrates for ATP synthesis. Although, there is evidence that both PIC and ANC are co-localized non-centrally with the c-ring in the Fo domain as an oblongated base piece [15]. Recent findings suggest that ATP synthase, ANC and PIC complex are present as separate entities [14]. The fibroblast samples of ATP synthase deficient patients showed  high content of ANC and PIC. A second evidence was shown in brown adipose tissue with a high content of these carriers, despite the tissue having low amount of ATP synthase [14]. Regardless of the location, their function appears to be the same. ANT functions as an antiporter, exchanges 1ADP for 1ATP. It transports the synthesized ATP from the matrix to the IMS and brings ADP in exchange into the matrix. The PIC operates as a symporter. It transports inorganic phosphate along with [H+] across the membrane, and the entry of Pi uses up the pH gradient [15, 16].

Dimerization of ATP synthase

Another important characteristic of ATP synthase in mitochondria is dimerization. Although the machine in its monomeric form is functional, they are susceptible to proteolysis, and the continuous function of the rotor and stator makes it easy to dissociate from the membrane [2, 17]. The dimer form provides support to the FOF1 complex. The ‘a-subunit’ provides the basis for dimerization and the accessory subunits e, f, g and A6L stabilize the monomer-monomer interface [2]. There are three other dimer-specific subunits associated with the FO domain such as subunit e/Tim11 (Su e/Tim11), subunit g homolog (Su g) and subunit k (Su k) essential for dimer formation in yeast [17]. The dimerization of ATP synthase causes a slight bend in the inner membrane that results in its protrusion into the matrix forming ‘cristae.’ A factor called IF1,in its mature form, contributes to this process, by stabilizing the F1 domains in the dimeric form [2]. The cristae formation results in a strong positive curvature due to the clustering of ATP synthase at the apex. The clustering generates a proton trap facilitating ATP synthesis. Thus, the mitochondrial ATP synthase optimizes its function of ATP production by self-organizing into a spatial arrangement [2] [17].

Visualization Techniques

A direct observation of ATP synthase mechanism is possible by connecting an actin filament to the -subunit [18]. A complex containing 3, 3 and  subunits is fixed to a surface bound bead of 0.2 m in diameter through histidine tags. These tags are linked to the amino terminus of each -subunit. Then, a fluorescently labeled actin filament is attached to the -subunit through streptavidin. The addition of ATP results in a counter-clockwise rotation of the fluorescent actin carrying filament [7]. The rotation of the c-ring can be observed similarly, by fixing 3, 3 subunits on a glass surface and attaching the actin filament to the c-subunit. Rotation, by ATP addition, is observed in E. coli under conditions, where the glutamate residues present in the c-subunits is replaced with cysteine [18]. This cysteine is then biotinylated to bind to streptavidin and attached to fluorescently labeled actin filament. The cysteine present in the  subunit is replaced with alanine to avoid the binding of the actin filament to  subunit. Protein immunoblotting with streptavidin confirmed the specific biotinylation. The addition of Mg-ATP resulted in the rotation of the actin filament connected to the c-subunit in E. coli [18]. The time course of rotation of the c-subunits is obtained by video images taken during centroid analysis of the actin filaments connected to the c-ring.

While X-ray crystallography, single particle cryo-Electron Microscopy, and Nuclear Magnetic Resonance studies have provided structural information of both Fo and F1 domains at high resolution [5] [19], the arrangement of ATP synthase in a dimeric form cannot be visualized by these techniques at a high resolution [19]. The method that can be used to study the dimeric arrangement is called electron cryotomography (cryo-ET). This process reveals the morphology of mitochondria at a three-dimensional level. The arrangement of dimers in the form of rows along the structure of cristae can be visualized by positioning the sub-tomogram average of the dimers in a vesicle containing the segmented volume [19]. The positioning of dimers in a vesicle is possible by manually segmenting the membranes in tomographic volumes, that reveal the structure of cristae. Then, by imaging mitochondria from different strains of yeast, cristae morphology can be visualized. Thus, cryo-ET of mitochondria not only determines high-resolution structure of the organelle, but also the arrangement and distribution of the proteins within them in the membrane [19].

Homeostasis and Stress

Mitochondria, initially derived from proteobacteria, maintain their bacterial characteristics in their ability to produce ATP[20]. However, during evolution, many of the bacterial genes from mitochondria were transferred to the nuclear genome. Mitochondrial DNA encodes only about 13 proteins, and these proteins constitute the ETC complexes I, III and IV. Complex II, however, is encoded by the nuclear genome [20]. Hence, the mitochondria and nucleus must coordinate continuously for transcription, translation, and import of mitochondrial proteins [20]. An ‘anterograde regulation’ is when nucleus tightly controls mitochondria, and a ‘retrograde regulation’ is when mitochondrial send signals to alter the nuclear gene expression. The communication between them helps the cells to maintain homeostasis and adapt to various stress responses [20].

Anterograde responses are activated when a change in metabolic conditions are detected. During exercise or calorie restriction, a decrease in ATP synthesis increases the AMP/ATP ratio resulting in the activation Adenosine Mono phosphate-activated protein kinase (AMPK). Activated AMPK, in turn, activates cellular [NAD+], which leads to the activation of [NAD+] dependent deacetylase called SIRT1 [21]. SIRT1 positively regulates PGC1 (a key regulator of energy metabolism) resulting in the activation of energy metabolism (ATP synthesis) [20] [21].

Retrograde responses can be categorized into Ca2+ dependent stress response, energetic stress response or reactive oxygen species(ROS) response [20].

A mutation or loss of mtDNA can disrupt Oxidative Phosphorylation by disrupting ETC complexes. This, in turn, results in the loss of mitochondrial , causing the release of Ca2+ into the cytosol [22]. The increased levels of cytosolic Ca2+ activate NFB through the activation of calcineurin [23]. NFB then migrates to the nucleus and promotes synthesis of proteins involved in Ca2+ transport and storage [20, 23].

Energetic stress responses are linked to mTOR [(mechanistic target of Rapamycin)- a serine/threonine protein kinase] and AMPK, where a decrease in ATP synthesis activates AMPK [21]. AMPK triggers the quality control system of mitochondria and induces degradation of defective mitochondria by autophagy [20] [24]. Similarly, when cells are under stress such as nutrient limitation, there is a decrease in mTOR activity. The decrease of mTOR facilitates retrograde signaling allowing the nuclear gene expression to be altered accordingly, whereas the activation of mTOR would inhibit this response [20] [25].

ROS are produced in mitochondria in response to a defective ETC. Increased levels of ROS can activate NFB and thus promote proliferation and survival of cancer cells [26]. However, when ROS increases, only up to a level that is not harmful to cells, it promotes JNK- PGC1 signaling and induces the expression of genes involved in oxidative phosphorylation [27].

 

Biogenesis, Mutations, and Disorders

The genes involved in oxidative phosphorylation include several nuclear-encoded transcription factors that act on mtDNA or the nucleus. A particular transcriptional control present on c-subunit of ATP synthase regulates the abundance of the whole enzyme in Brown Adipose Tissue [3]. Upon cold acclimation in this tissue, the content of ATP synthase is reduced by 10-fold, while the rest of the enzymes involved in OXPHOS are highly abundant [28]. The abundance of enzymes, results in the proton flow across the inner membrane and they get converted to heat instead of ATP. This process is facilitated by an uncoupling protein (UCP1 or Thermogenin) [29]. The transcriptional regulation of UCP1 has proven to be crucial to know the ATP synthase content in brown adipose tissue. Since UCP1 levels correlate with the mRNA levels of c-subunit, the transcriptional regulation of c-subunit alone can be a general mechanism to the amount of ATP synthase in human cells [28] [3].

Mutations in genes encoding the mitochondrial ATP synthase lead to several disorders. One such example is a mutation in ATP8 gene, which encodes A6L subunit in the Fo domain [2]. A nonsense mutation in ATP8 gene has been detected a sixteen-year-old patient suffering from neuropathy and hypertrophic cardiomyopathy [30]. ATP6 and ATP8 genes code for ‘subunit-a’ and ‘subunit-A6L’ respectively [2]. The ATP8 mutation is in the overlapping region of ATP6 and ATP8. The mutation in this region, results in a premature stop codon induced in ATP8, due to a silent change in the initiator codon (methionine) of ATP6 [3]. The induction of a stop codon leads a truncated form of A6L, lacking a chunk of amino acids in its C-terminal region. Due to this, the patient’s fibroblast and muscle tissues showed an accumulation of synthase sub-complexes due to a partially assembled ATP synthase with a decreased ATP synthesis rate [3, 30].

Several ATP6 gene point mutations are associated with an early onset of maternally inherited neurodegenerative syndromes. The most common mutation is a thymine to cytosine mutation at 8993 position, where Leu-156 is converted to Proline [31]. This mutation leads to Neuropathy, Ataxia and Retinitis pigmentosa (NARP syndrome) and a maternally inherited Leigh Syndrome(MILS) [32]. Patients with this mutation have a slightly lower rate of ATP synthesis. However, muscle biopsies from patients suffering from 95% of this alteration were observed to have impaired ATP synthase assembly. Some suggestions are made considering ROS to be the pathogenic factor causing the oxidative damage of cells [31] [33].

Another example of ATP6 gene mutation is T9101C, converting Leucine-192 to Threonine, seen in patients suffering from a maternally inherited eye disease called Leber’s hereditary optic neuropathy(LHON). LHON causes bilateral optic atrophy in young adults [34]. The T9101C mutation causes proton leakage and reduces the efficiency of OXPHOS. However, a replacement of Threonine by Isoleucine-192 led to a bio-energetic alteration [3, 34].

Inhibitors of ATP synthase

Oligomycins are natural macrolides, belonging to the class of polyketide inhibitors [31]. They bind to mitochondrial ATP synthase at the interface of a and c-subunit, involving Gly23 and Glu59 of N and C-terminal transmembrane helices of c-subunit [35]. Since Glu59 plays a critical role in proton translocation [3], Oligomycin, targeting the region of Glu59, prevents the movement of protons across the channel and thus inhibits ATP synthesis [31].

IF1 is a natural -helical regulatory peptide found in mitochondria [31]. It inhibits ATP hydrolysis by binding to the F1 domain [36]. IF1 binding is non-competitive and reversible. It requires the presence of ATP to bind to the F1 domain and hence it does not affect the process of ATP synthesis. The crystal structure of F1 domain with IF1, revealed the binding of N-terminus region of IF1 to DP and DP subunits, along with TP, E, and -subunit [36]. IF1 plays its role of inhibition, by obstructing the closure of DP-DP catalytic interfaces, to prevent ATP hydrolysis [31].

N, N– dicyclohexylcarbodiimide (DCCD) are compounds containing N=C=C functional groups[31]. They modify carboxyl groups within F1 domain and inhibits the function of ATPase. One molecule of DCCD inhibits 95% of ATPase activity in the F1 domain. It reacts covalently with DP subunit,specifically at Glu199, present at the interface of DP and DP subunits [37]. The binding of DCCD covalently modifies Glu199 and blocks the conformational change from DP to E and thus prevents the hydrolysis of ATP [31] [37].

Conclusions

Mitochondrial ATP synthase functions as a molecular machine to generate ATP from ADP and Pi using the energy derived from an electro chemical [H+] gradient [1]. The ATP synthase reverses its function, in the absence of a [H+] gradient, by hydrolyzing ATP and pumping protons back into the inter membrane space [2]. The proton gradient is generated by the electron transport chain that carries electrons derived from NADH molecules and simultaneously pumps protons from the matrix to the intermembrane space. The oxidation of 1 NADH molecule pumps 10 [H+], which is sufficient to synthesize 3 ATP molecules [4]. The dimeric form of Complex V stabilizes the complex by the formation of cristae and generates a proton trap, facilitating ATP synthesis [2]. There are ANC and PIC complexes, that act as antiporters and symporters respectively and bring in the substrates required to generate ATP [15]. Mitochondrial ATP synthase seems to play a major role in homeostasis and stress, where a decrease in the rate of ATP synthesis allows mitochondrial-nuclear communication through anterograde and retrograde signals to maintain homeostasis in cells and allow the cells to adapt to stress conditions [20]. Different classes of compounds such as Oligomycin, IF1 and DCCD inhibit the synthase complex [31] and several point mutations in genes encoding the protein machine, can lead to disorders such as Leber’s Hereditary Optic Myopathy, NARP syndrome and Leigh syndrome [3].

 

 

 

References

1. Balzani, V.V., et al., Artificial Molecular Machines. Angew Chem Int Ed Engl, 2000. 39(19): p. 3348-3391.

2. Jonckheere, A.I., J.A.M. Smeitink, and R.J.T. Rodenburg, Mitochondrial ATP synthase: architecture, function and pathology. Journal of Inherited Metabolic Disease, 2012. 35(2): p. 211-225.

3. Kucharczyk, R., et al., Mitochondrial ATP synthase disorders: Molecular mechanisms and the quest for curative therapeutic approaches. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 2009. 1793(1): p. 186-199.

4. Watt, I.N., et al., Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proceedings of the National Academy of Sciences of the United States of America, 2010. 107(39): p. 16823-16827.

5. Boyer, P.D., The ATP synthase–a splendid molecular machine. Annu Rev Biochem, 1997. 66: p. 717-49.

6. Nakamoto, R.K., J.A. Baylis Scanlon, and M.K. Al-Shawi, The rotary mechanism of the ATP synthase. Archives of Biochemistry and Biophysics, 2008. 476(1): p. 43-50.

7. Yasuda, R., et al., F1-ATPase Is a Highly Efficient Molecular Motor that Rotates with Discrete 120° Steps. Cell, 1998. 93(7): p. 1117-1124.

8. Preiss, L., et al., The c-ring stoichiometry of ATP synthase is adapted to cell physiological requirements of alkaliphilic Bacillus pseudofirmus OF4. Proceedings of the National Academy of Sciences of the United States of America, 2013. 110(19): p. 7874-7879.

9. Dimroth, P., G. Kaim, and U. Matthey, Crucial role of the membrane potential for ATP synthesis by F(1)F(o) ATP synthases. Journal of Experimental Biology, 2000. 203(1): p. 51.

10. Mitchell, P., Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Biochimica et Biophysica Acta (BBA) – Bioenergetics, 2011. 1807(12): p. 1507-1538.

11. von Ballmoos, C., G.M. Cook, and P. Dimroth, Unique rotary ATP synthase and its biological diversity. Annu Rev Biophys, 2008. 37: p. 43-64.

12. Subramanian, S., et al., Comparative energetics and kinetics of autotrophic lipid and starch metabolism in chlorophytic microalgae: implications for biomass and biofuel production. Biotechnology for Biofuels, 2013. 6(1): p. 150.

13. Pänke, O. and B. Rumberg, Energy and entropy balance of ATP synthesis. Biochimica et Biophysica Acta (BBA) – Bioenergetics, 1997. 1322(2): p. 183-194.

14. Nůsková, H., et al., Mitochondrial ATP synthasome: Expression and structural interaction of its components. Biochemical and Biophysical Research Communications, 2015. 464(3): p. 787-793.

15. Chen, C., et al., Mitochondrial ATP Synthasome: THREE-DIMENSIONAL STRUCTURE BY ELECTRON MICROSCOPY OF THE ATP SYNTHASE IN COMPLEX FORMATION WITH CARRIERS FOR Pi AND ADP/ATP. Journal of Biological Chemistry, 2004. 279(30): p. 31761-31768.

16. Klingenberg, M., The ADP and ATP transport in mitochondria and its carrier. Biochimica et Biophysica Acta (BBA) – Biomembranes, 2008. 1778(10): p. 1978-2021.

17. Arnold, I., et al., Yeast mitochondrial F1F0-ATP synthase exists as a dimer: identification of three dimer-specific subunits. Embo j, 1998. 17(24): p. 7170-8.

18. Sambongi, Y., et al., Mechanical Rotation of the c Subunit Oligomer in ATP Synthase (F<sub>0</sub>F<sub>1</sub>): Direct Observation. Science, 1999. 286(5445): p. 1722.

19. Davies, K.M., et al., Visualization of ATP Synthase Dimers in Mitochondria by Electron Cryo-tomography. Journal of Visualized Experiments : JoVE, 2014(91): p. 51228.

20. Quiros, P.M., A. Mottis, and J. Auwerx, Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol, 2016. 17(4): p. 213-26.

21. Garcia-Roves, P.M., et al., Gain-of-function R225Q mutation in AMP-activated protein kinase gamma3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J Biol Chem, 2008. 283(51): p. 35724-34.

22. Luo, Y., J.D. Bond, and V.M. Ingram, Compromised mitochondrial function leads to increased cytosolic calcium and to activation of MAP kinases. Proceedings of the National Academy of Sciences of the United States of America, 1997. 94(18): p. 9705-9710.

23. Biswas, G., et al., Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta. J Cell Biol, 2003. 161(3): p. 507-19.

24. Egan, D.F., et al., Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science (New York, N.Y.), 2011. 331(6016): p. 456-461.

25. Lerner, C., et al., Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts. Aging Cell, 2013. 12(6): p. 966-77.

26. Formentini, L., et al., The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell, 2012. 45(6): p. 731-42.

27. Chae, S., et al., A systems approach for decoding mitochondrial retrograde signaling pathways. Sci Signal, 2013. 6(264): p. rs4.

28. Kramarova, T.V., et al., Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-Fo subunit P1 isoform. Faseb j, 2008. 22(1): p. 55-63.

29. Cannon, B. and J. Nedergaard, Brown adipose tissue: function and physiological significance. Physiol Rev, 2004. 84(1): p. 277-359.

30. Jonckheere, A.I., et al., A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. J Med Genet, 2008. 45(3): p. 129-33.

31. Hong, S. and P.L. Pedersen, ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas. Microbiology and Molecular Biology Reviews : MMBR, 2008. 72(4): p. 590-641.

32. de Vries, D.D., et al., A second missense mutation in the mitochondrial ATPase 6 gene in Leigh’s syndrome. Ann Neurol, 1993. 34(3): p. 410-2.

33. Baracca, A., et al., Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993. Biochim Biophys Acta, 2007. 1767(7): p. 913-9.

34. Lamminen, T., et al., A mitochondrial mutation at nt 9101 in the ATP synthase 6 gene associated with deficient oxidative phosphorylation in a family with Leber hereditary optic neuroretinopathy. Am J Hum Genet, 1995. 56(5): p. 1238-40.

35. John, U.P. and P. Nagley, Amino acid substitutions in mitochondrial ATPase subunit 6 of Saccharomyces cerevisiae leading to oligomycin resistance. FEBS Letters, 1986. 207(1): p. 79-83.

36. Cabezon, E., et al., The structure of bovine F1-ATPase in complex with its regulatory protein IF1. Nat Struct Biol, 2003. 10(9): p. 744-50.

37. Gibbons, C., et al., The structure of the central stalk in bovine F(1)-ATPase at 2.4 A resolution. Nat Struct Biol, 2000. 7(11): p. 1055-61.

 

 

 

 

 

 

Cite This Work

To export a reference to this article please select a referencing stye below:

Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.

Related Services

View all

DMCA / Removal Request

If you are the original writer of this essay and no longer wish to have the essay published on the UK Essays website then please:

McAfee SECURE sites help keep you safe from identity theft, credit card fraud, spyware, spam, viruses and online scams Prices from
£29

Undergraduate 2:2 • 250 words • 7 day delivery

Order now

Delivered on-time or your money back

Rated 4.0 out of 5 by
Reviews.co.uk Logo (23 Reviews)

Get help with your dissertation