Topology of the mitochondrial cAMP‐dependent protein kinase and its substrates

Sardanelli, Anna Maria; Technikova-Dobrova, Zuzana; Speranza, Francesco; Mazzocca, Antonio; Scacco, Salvatore; Papa, Sergio

doi:10.1016/0014-5793(96)01112-x

Cited by 54 publications

(45 citation statements)

References 9 publications

(23 reference statements)

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“…An mtPKA has also been detected in yeast mitochondria [1 1]. It was found [12] that a protein of apparent M r 18 kDa phosphorylated by mtPKA in the inner membrane of bovine heart mitochondria [8] is associated to complex I. In this paper *Corresponding author.…”

Section: Introductionmentioning

confidence: 88%

The nuclear‐encoded 18 kDa (IP) AQDQ subunit of bovine heart complex I is phosphorylated by the mitochondrial cAMP‐dependent protein kinase

et al. 1996

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In bovine heart mitochondria a protein of M, 18 kDa, phosphorylated by mtPKA, is associated to the NADH-ubiquinone oxidoreductase in the inner membrane and is present in purified preparation of this complex. The 18 kDa phosphoprotein has now been isolated and sequenced. It is identified as the 18 kDa (IP) AQDQ subnnit of complex I, a protein of 133 amino acids with a phospborylation consensus site RVS at position 129-131.

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Section: Introductionmentioning

confidence: 88%

The nuclear‐encoded 18 kDa (IP) AQDQ subunit of bovine heart complex I is phosphorylated by the mitochondrial cAMP‐dependent protein kinase

et al. 1996

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“…The observed loss of activity of complex 1 with elevated levels of ROS has been suggested to be the result of PKA-altered phosphorylation of the 18-kDa subunit [192]. Anchored via A-kinase-anchoring protein [193] to numerous cellular locations including the mitochondria [194], PKA has been suggested to be localized to the mitochondrial matrix and IMM [195][196][197][198], where it has been shown to phosphorylate the 29-and 6.5-kDa subunits of complex 1 [199]. The regulation of activity of these proteins, however, is not understood.…”

Section: Mitochondrial Signalingmentioning

confidence: 99%

Mitochondria: A mirror into cellular dysfunction in heart disease

White

Edwards

Cordwell

et al. 2008

Proteomics Clinical Apps

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Cardiovascular (CV) disease is the single most significant cause of morbidity and mortality worldwide. The emerging global impact of CV disease means that the goals of early diagnosis and a wider range of treatment options are now increasingly pertinent. As such, there is a greater need to understand the molecular mechanisms involved and potential targets for intervention. Mitochondrial function is important for physiological maintenance of the cell, and when this function is altered, the cell can begin to suffer. Given the broad range and significant impacts of the cellular processes regulated by the mitochondria, it becomes important to understand the roles of the proteins associated with this organelle. Proteomic investigations of the mitochondria are hampered by the intrinsic properties of the organelle, including hydrophobic mitochondrial membranes; high proportion of basic proteins (pI greater than 8.0); and the relative dynamic range issues of the mitochondria. For these reasons, many proteomic studies investigate the mitochondria as a discrete subproteome. Once this has been achieved, the alterations that result in functional changes with CV disease can be observed. Those alterations that lead to changes in mitochondrial function, signaling and morphology, which have significant implications for the cardiomyocyte in the development of CV disease, are discussed.

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“…The presence of PKA and PKC activities in the mitochondrial inner membrane-matrix compartment and the role of PKC-mediated phosphorylation in the regulation of pyruvate dehydrogenase activity are well established (16). An 18-kDa subunit of the NADH dehydrogenase (complex I) (17) and subunits I, II, and Vb of CcO (complex IV) are phosphorylated in vitro when incubated with PKA and [␥- 32 P]ATP (18).…”

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Protein Kinase A-mediated Phosphorylation Modulates Cytochrome c Oxidase Function and Augments Hypoxia and Myocardial Ischemia-related Injury

Prabu

Anandatheerthavarada

Raza³

et al. 2006

Journal of Biological Chemistry

166

195

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We have investigated the effects of hypoxia and myocardial ischemia/reperfusion on the structure and function of cytochrome c oxidase (CcO). Hypoxia (0.1% O 2 for 10 h) and cAMP-mediated inhibition of CcO activity were accompanied by hyperphosphorylation of subunits I, IVi1, and Vb and markedly increased reactive O 2 species production by the enzyme complex in an in vitro system that uses reduced cytochrome c as an electron donor. Both subunit phosphorylation and enzyme activity were effectively reversed by 50 nM H89 or 50 nM myristoylated peptide inhibitor (MPI), specific inhibitors of protein kinase A, but not by inhibitors of protein kinase C. In rabbit hearts subjected to global and focal ischemia, CcO activity was inhibited in a time-dependent manner and was accompanied by hyperphosphorylation as in hypoxia. Additionally, CcO activity and subunit phosphorylation in the ischemic heart were nearly completely reversed by H89 or MPI added to the perfusion medium. Hyperphosphorylation of subunits I, IVi1, and Vb was accompanied by reduced subunit contents of the immunoprecipitated CcO complex. Most interestingly, both H89 and MPI added to the perfusion medium dramatically reduced the ischemia/reperfusion injury to the myocardial tissue. Our results pointed to an exciting possibility of using CcO activity modulators for controlling myocardial injury associated with ischemia and oxidative stress conditions. Cytochrome c oxidase (CcO) 3 is the terminal oxidase of the mitochondrial electron transport chain, whose activity is modulated in response to O 2 tension and the work load of the tissue (1-6). This rate-limiting enzyme is an important site of regulation of mitochondrial respiration and oxidative phosphorylation (7). In the yeast, altered CcO activity in response to aerobic and anaerobic conditions is associated with the differential expression of the two isologs of the CcO Vb gene (8), although the precise mechanism by which the mammalian CcO modulates its activity remains unknown. Mitochondrial electron transport chain complexes are major sources of cellular ROS under both normoxic and hypoxic conditions (9, 10). Hypoxia-tolerant and hypoxia-sensitive human glioma cells exhibit distinct patterns of mitochondrial function in response to hypoxia (9, 11). Submitochondrial particles exposed to hypoxic conditions in vitro show reduced CcO activity (1,10,12). Some studies also suggest that the myocardial ischemia/reperfusion injury is manifested through altered CcO activity and reduced mitochondrial oxidative phosphorylation (13,14).Protein kinases have been suggested to play a role in the modulation of myocardial ischemia/reperfusion injury (15), although the roles of different cellular components in mediating this injury remain unclear. The presence of PKA and PKC activities in the mitochondrial inner membrane-matrix compartment and the role of PKC-mediated phosphorylation in the regulation of pyruvate dehydrogenase activity are well established (16). An 18-kDa subunit of the NADH dehydrogenase (complex I) (17)...

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Topology of the mitochondrial cAMP‐dependent protein kinase and its substrates

Cited by 54 publications

References 9 publications

The nuclear‐encoded 18 kDa (IP) AQDQ subunit of bovine heart complex I is phosphorylated by the mitochondrial cAMP‐dependent protein kinase

The nuclear‐encoded 18 kDa (IP) AQDQ subunit of bovine heart complex I is phosphorylated by the mitochondrial cAMP‐dependent protein kinase

Mitochondria: A mirror into cellular dysfunction in heart disease

Protein Kinase A-mediated Phosphorylation Modulates Cytochrome c Oxidase Function and Augments Hypoxia and Myocardial Ischemia-related Injury

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