Respiratory chain complex I, a main regulatory target of the cAMP/PKA pathway is defective in different human diseases

Papa, Sergio; Rasmo, Domenico De; Technikova-Dobrova, Zuzana; Panelli, Damiano; Signorile, Anna; Scacco, Salvatore; Petruzzella, Vittoria; Papa, Francesco; Palmisano, Giuseppe; Gnoni, Antonio; Micelli, Loris; Sardanelli, Anna Maria

doi:10.1016/j.febslet.2011.09.019

Cited by 67 publications

(51 citation statements)

References 116 publications

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“…PINK1 may also regulate mitochondrial biology through activation of protein kinase A (PKA) (26). PKA regulates the biosynthesis of mtDNA encoded proteins, and enhances complex I activity through direct phosphorylation of the NDUFS4 subunit (85). Notably, AKAP1-mediated targeting of endogenous PKA to mitochondria reverses the respiratory and ATP deficits in PINK1-deficient mammalian cells (25).…”

Section: Pink1mentioning

confidence: 99%

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Steer

Dail

Chu

2015

Antioxidants & Redox Signaling

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Significance: Disruptions in mitochondrial homeostasis are implicated in human diseases across the lifespan. Recessive mutations in PINK1, which encodes the mitochondrially targeted PTEN-induced putative kinase 1 (PINK1), cause an autosomal recessive form of Parkinson's disease. As with all kinases, PINK1 participates in multiple functional pathways, and its dysregulation has been implicated in a growing number of diseases. Recent Advances: In addition to its heavily studied role in mitophagy, PINK1 regulates mitochondrial respiratory function, reactive oxygen species generation, and mitochondrial transport. Moreover, recent studies implicate processed PINK1 in cytosolic signaling cascades that promote cell survival and neuron differentiation. Cytosolic PINK1 is also capable of suppressing autophagy and mitophagy. We propose a working hypothesis that PINK1 is released by functional mitochondria as a signal to coordinate cell growth and differentiation in response to mitochondrial status. Critical Issues: PINK1 biology needs to be better understood in primary neurons, as the stability and subcellular localization of PINK1 is differentially regulated in different cell types. Delineating factors that regulate its mitochondrial import/export, processing by different peptidases, kinase activity, subcellular localization, and degradation will be important for defining relevant downstream kinase targets. Future Directions: It is becoming clear that different subcellular pools of PINK1 mediate distinct functions. Future studies will undoubtedly expand on the spectrum of cellular functions regulated by PINK1. Continued study of cytosolic PINK1 may offer novel insights into how functional mitochondria communicate their status with the rest of the cell. Antioxid. Redox Signal. 22, 1047-1059. P arkinson's disease (PD) is a debilitating age-related neurodegenerative disorder that affects 4-5 million people in the world's most populous nations (28). PD pathology is characterized by: (i) Lewy body inclusions, which contain alpha-synuclein and ubiquitin, in autonomic, brainstem and cortical regions (10), and (ii) the loss of pigmented brain stem neurons from the substantia nigra and locus ceruleus. Degeneration of dopaminergic nigral neurons account for the classic motor signs, although other neuron groups are also affected. While the majority of PD cases are idiopathic, studies of gene products implicated in familial PD implicate common pathways that are likely to be important for disease progression (101).Mutations in PINK1, which encodes PTEN-induced putative kinase 1 (PINK1), represent the second most common cause of autosomal recessive parkinsonism (48,103). PINK1 families exhibit an earlier onset of disease (range of 9-52 years), accompanied by sustained responses to levodopa treatment (9,57,64,103). Autopsy findings have been reported from one family, showing classic Lewy body pathology (92). Pathways regulated by PINK1 appear to interact with other PD-linked genes (11,20,91), and PINK1 enhances the resistance of...

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Section: Pink1mentioning

confidence: 99%

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Steer

Dail

Chu

2015

Antioxidants & Redox Signaling

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“…Indeed, recent reviews have models locating this enzyme in the intermembrane space (66), whereas others propose a matrix-PKA (155). Most recently, Means et al (134) provided convincing evidence that one of prominent substrates for PKA is the intermembrane helix protein ChChd3, supporting the notion of its localization outside the matrix.…”

Section: Mitochondrial Matrix Protein Kinasesmentioning

confidence: 98%

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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“…Furthermore, we limit ourselves to models that involve mutations in, or deletion of, the Ndufs4 gene. The latter encodes an 18-kDa protein, the NDUFS4 (NADH dehydrogenase [ubiquinone] iron-sulfur protein 4) accessory subunit of CI (OMIM 602694) (3)(4)(5). In humans, CI consists of 44 different subunits that combine into the CI holo-complex to form a 1 MDa assembly (2,6).…”

Section: Introductionmentioning

confidence: 99%

“…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). Below, we first summarize the results obtained with patientderived fibroblasts ensuing from Ndufs4 mutations and/or deletion (Human CI Deficiency Due to NDUFS4 Mutations: Patient Fibroblasts section).…”

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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Respiratory chain complex I, a main regulatory target of the cAMP/PKA pathway is defective in different human diseases

Cited by 67 publications

References 116 publications

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

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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