Phosphorylation pattern of the NDUFS4 subunit of complex I of the mammalian respiratory chain

Rasmo, Domenico De; Palmisano, Giuseppe; Scacco, Salvatore; Technikova-Dobrova, Zuzana; Panelli, Damiano; Cocco, Tiziana; Sardanelli, Anna Maria; Gnoni, Antonio; Micelli, Loris; Trani, Antonio; Luccia, Aldo Di; Papa, Sergio

doi:10.1016/j.mito.2010.04.005

Cited by 41 publications

(39 citation statements)

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“…Previous work from our laboratory has shown that phosphorylation of the C-terminal RVS conserved site of the nuclear-encoded NDUFS4 subunit of complex I [20] by extramitochondrial PKA promotes the membrane potential driven mitochondrial import of the precursor form of the protein [21]. The imported precursor, processed by mitochondrial maturase with cleavage of the positively charged leader sequence, generates the mature form which is then incorporated in the complex (see Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Other investigations showed that phosphorylation by extramitochondrial PKA of serine in the C-terminus RVS conserved site of the nuclear-encoded NDUFS4 subunit of complex I [19,20] promotes mitochondrial import and maturation of the precursor form of the protein and prevents retrograde back diffusion in the cytosol of the mature form of the protein [21].…”

Section: Introductionmentioning

confidence: 99%

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Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Rasmo¹,

Signorile²,

Santeramo³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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In mammalian cells the nuclear-encoded subunits of complex I are imported into mitochondria, where they are assembled with mt-DNA encoded subunits in the complex, or exchanged with pre-existing copies in the complex. The present work shows that in fibroblast cultures inhibition by KH7 of cAMP production in the mitochondrial matrix by soluble adenylyl cyclase (sAC) results in decreased amounts of free non-incorporated nuclear-encoded NDUFS4, NDUFV2 and NDUFA9 subunits of the catalytic moiety and inhibition of the activity of complex I. Addition of permeant 8-Br-cAMP prevents this effect of KH7. KH7 inhibits accumulation in isolated rat-liver mitochondria and incorporation in complex I of "in vitro" produced, radiolabeled NDUFS4 and NDUFV2 subunits. 8-Br-cAMP prevents also this effect of KH7. Use of protease inhibitors shows that intramitochondrial cAMP exerts this positive effect on complex I by preventing digestion of nuclear-encoded subunits by mitochondrial protease(s), whose activity is promoted by KH7 and H89, an inhibitor of PKA.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Rasmo¹,

Signorile²,

Santeramo³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…In the case of Ser173 of NDUFS4, at least a correlation has been observed between the amount of imported protein and the phosphorylation of this residue by PKA (54,55). Ser96 of NDUFA7 was found to be phosphorylated in bovine heart (165), although phosphopeptide enrichment was needed to detect it, as was the case with Ser78 of NDUFA2, found in mouse brown fat, heart, kidney, and brain (94,222), suggesting a very low mole fraction of phosphorylation.…”

Section: Mitochondrial Matrix Protein Kinases)mentioning

confidence: 99%

“…However, it could be argued that these phosphorylation sites are important for protein import and, consequently, affect steady-state levels of mitochondrial complexes. Except for a few isolated cases, such as NDUFS4 at a site within the mature protein (54,55) and several subunits of the translocase of the outer membrane (TOM) complex (170,191), phosphorylation has not been correlated with protein import to mitochondria. An interesting example is the ␤-subunit of complex V, where a significant amount of phosphorylated precursor was detected when cAMP levels were increased by treatment of mouse lymphoma cells with isoproterenol (202).…”

Section: Introductionmentioning

confidence: 99%

Cardiac mitochondrial matrix and respiratory complex protein phosphorylation

Covián

Balaban

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Covian R, Balaban RS. Cardiac mitochondrial matrix and respiratory complex protein phosphorylation. Am J Physiol Heart Circ Physiol 303: H940 -H966, 2012. First published August 10, 2012; doi:10.1152/ajpheart.00077.2012.-It has become appreciated over the last several years that protein phosphorylation within the cardiac mitochondrial matrix and respiratory complexes is extensive. Given the importance of oxidative phosphorylation and the balance of energy metabolism in the heart, the potential regulatory effect of these classical signaling events on mitochondrial function is of interest. However, the functional impact of protein phosphorylation and the kinase/phosphatase system responsible for it are relatively unknown. Exceptions include the well-characterized pyruvate dehydrogenase and branched chain ␣-ketoacid dehydrogenase regulatory system. The first task of this review is to update the current status of protein phosphorylation detection primarily in the matrix and evaluate evidence linking these events with enzymatic function or protein processing. To manage the scope of this effort, we have focused on the pathways involved in energy metabolism. The high sensitivity of modern methods of detecting protein phosphorylation and the low specificity of many kinases suggests that detection of protein phosphorylation sites without information on the mole fraction of phosphorylation is difficult to interpret, especially in metabolic enzymes, and is likely irrelevant to function. However, several systems including protein translocation, adenine nucleotide translocase, cytochrome c, and complex IV protein phosphorylation have been well correlated with enzymatic function along with the classical dehydrogenase systems. The second task is to review the current understanding of the kinase/phosphatase system within the matrix. Though it is clear that protein phosphorylation occurs within the matrix, based on 32 P incorporation and quantitative mass spectrometry measures, the kinase/phosphatase system responsible for this process is ill-defined. An argument is presented that remnants of the much more labile bacterial protein phosphoryl transfer system may be present in the matrix and that the evaluation of this possibility will require the application of approaches developed for bacterial cell signaling to the mitochondria.kinase; phosphatase; citric acid cycle; oxidative phosphorylation; protein transport; mitochondria intermembrane space; phosphohistidine; adenine nucleotide translocase; pyruvate dehydrogenase; branched chain ␣-ketoacid dehydrogenase THIS REVIEW ARTICLE is part of a collection on Post-translational Protein Modification in Metabolic Stress. Other articles appearing in this collection, as well as a full archive of all Review collections, can be found online at http://ajpheart. physiology.org/.

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“…Evidence was provided that several CI subunits can be phosphorylated by cyclic AMP (cAMP)-dependent protein kinase A (PKA) (10). In case of NDUFS4, its phosphorylation site has been localized at the C-terminal end of the protein (amino acids 171-173: RVSTK) in human fibroblasts (11). Phosphorylation of RVSTK appears to promote import and maturation of the precursor protein (12), thereby affecting CI assembly and activity (5).…”

Section: Introductionmentioning

confidence: 99%

Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit

et al. 2013

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To allow the rational design of effective treatment strategies for human mitochondrial disorders, a proper understanding of their biochemical and pathophysiological aspects is required. The development and evaluation of these strategies require suitable model systems. In humans, inherited complex I (CI) deficiency is one of the most common deficiencies of the mitochondrial oxidative phosphorylation system. During the last decade, various cellular and animal models of CI deficiency have been presented involving mutations and/or deletion of the Ndufs4 gene, which encodes the NDUFS4 subunit of CI. In this review, we discuss these models and their validity for studying human CI deficiency.

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Phosphorylation pattern of the NDUFS4 subunit of complex I of the mammalian respiratory chain

Cited by 41 publications

References 40 publications

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Cardiac mitochondrial matrix and respiratory complex protein phosphorylation

Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit

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