Evidence of undiscovered cell regulatory mechanisms: phosphoproteins and protein kinases in mitochondria

Thomson, Murray

doi:10.1007/s00018-002-8417-7

Cited by 79 publications

(60 citation statements)

References 71 publications

(91 reference statements)

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“…Cox activity is also regulated by phosphorylation and dephosphorylation. As many as at least ten of the 13 subunits of Cox could be phosphorylated at serine and/or threonine residues (Thompson 2002). As seen from our proteomics results, we found that serine/threonine-protein phosphatase 1 decreased in leucine-treated INS-1E cells (Table 1).…”

Section: Discussionsupporting

confidence: 69%

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

Liu

Jeppesen

Gregersen

et al. 2012

Journal of Endocrinology

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Chronic hyperglycemia and hyperlipidemia cause deleterious effects on b-cell function. Interestingly, increased circulating amino acid (AA) levels are also a characteristic of the prediabetic and diabetic state. The chronic effects of AAs on b-cell function remain to be determined. Isolated mouse islets and INS-1E cells were incubated with or without excess leucine. After 72 h, leucine increased basal insulin secretion and impaired glucose-stimulated insulin secretion in both mouse islets and INS-1E cells, corroborating the existence of aminoacidotoxicity-induced b-cell dysfunction. This took place concomitantly with alterations in proteins and genes involved in insulin granule transport, trafficking (e.g. collapsin response mediator protein 2 and GTP-binding nuclear protein Ran), insulin signal transduction (proteasome subunit a type 6), and the oxidative phosphorylation pathway (cytochrome c oxidase). Leucine downregulated insulin 1 gene expression but upregulated pancreas duodenum homeobox 1 and insulin 2 mRNA expressions. Importantly, cholesterol (CH) accumulated in INS-1E cells concomitantly with upregulation of enzymes involved in CH biosynthesis (e.g. 3-hydroxy-3-methylglutaryl-CoA reductase, mevalonate (diphospho) decarboxylase, and squalene epoxidase) and LDL receptor, whereas triglyceride content was decreased. Our findings indicate that chronic exposure to elevated levels of leucine may have detrimental effects on both b-cell function and insulin sensitivity. Aminoacidotoxicity may play a pathogenic role in the development of type 2 diabetes.

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Section: Discussionsupporting

confidence: 69%

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

Liu

Jeppesen

Gregersen

et al. 2012

Journal of Endocrinology

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“…A number of recent studies have provided evidence that phosphorylation of mitochondrial proteins is much more frequent than expected (15)(16)(17)(18)(19)(20)(21)(22)(23). (i) Incubation of isolated mitochondria with radiolabeled ATP or staining of mitochondrial proteins with phosphospecific dyes suggested that a substantial fraction of mitochondrial proteins are phosphorylated (24 -27).…”

mentioning

confidence: 99%

Profiling Phosphoproteins of Yeast Mitochondria Reveals a Role of Phosphorylation in Assembly of the ATP Synthase

Reinders

Wagner

Zahedi

et al. 2007

Molecular & Cellular Proteomics

151

133

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Mitochondria are crucial for numerous cellular processes, yet the regulation of mitochondrial functions is only understood in part. Recent studies indicated that the number of mitochondrial phosphoproteins is higher than expected; however, the effect of reversible phosphorylation on mitochondrial structure and function has only been defined in a few cases. It is thus crucial to determine authentic protein phosphorylation sites from highly purified mitochondria in a genetically tractable organism. The yeast Saccharomyces cerevisiae is a major model organism for the analysis of mitochondrial functions. We isolated highly pure yeast mitochondria and performed a systematic analysis of phosphorylation sites by a combination of different enrichment strategies and mass spectrometry. We identified 80 phosphorylation sites in 48 different proteins. These mitochondrial phosphoproteins are involved in critical mitochondrial functions, including energy metabolism, protein biogenesis, fatty acid metabolism, metabolite transport, and redox regulation. By combining yeast genetics and in vitro biochemical analysis, we found that phosphorylation of a serine residue in subunit g (Atp20) regulates dimerization of the mitochondrial ATP synthase. The authentic phosphoproteome of yeast mitochondria will represent a rich source to uncover novel roles of reversible protein phosphorylation. Molecular & Cellular Proteomics 6:1896 -1906, 2007.Mitochondria are the central organelle for the energy metabolism of eukaryotic cells and are critical for numerous metabolic pathways, including that for amino acids, lipids, heme, and iron-sulfur clusters, and play key roles in the regulation of programmed cell death (1-5). It is evident that these processes have to be tightly regulated to permit a mitochondrial response to changes in energy demand, cellular metabolism, or environmental conditions (6, 7). Until recently the most common regulatory mechanism of eukaryotic cells, reversible phosphorylation (8 -10), was considered to represent an exception in the case of mitochondria, including the E1 subunit of pyruvate dehydrogenase and the branched-chain ␣-ketoacid dehydrogenase (11)(12)(13)(14).A number of recent studies have provided evidence that phosphorylation of mitochondrial proteins is much more frequent than expected (15-23). (i) Incubation of isolated mitochondria with radiolabeled ATP or staining of mitochondrial proteins with phosphospecific dyes suggested that a substantial fraction of mitochondrial proteins are phosphorylated (24 -27). A limitation of these approaches is the inability to identify the specific phosphorylated amino acid residues in addition to the possibility of nonspecific labeling of proteins.(ii) Proteomics analysis of isolated mitochondria by mass spectrometry revealed the presence of numerous protein kinases and phosphatases (28 -34), implying that reversible protein phosphorylation may be a widespread mechanism of regulating mitochondrial function. The most comprehensive proteomics analysis of mitochondria, the PROM...

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“…The endocrine, paracrine, autocrine, and even intracrine mechanisms that modulate this process are still to be described. No matter which one is the signaling pathway activated, the importance of the events of dynamic phosphorylation of proteins with pleiotropic effects in cellular functions as hormonal synthesis is the most relevant (Corso  Thomson, 2001;Gorostizaga et al, 2007;Thomson, 2002).…”

Section: The Role Of Mitochondria In the Phosphorylation Cell Signalingmentioning

confidence: 99%

“…StAR protein phosphorylation mediated by PKA stimulates the transport of cholesterol from the cytoplasm into mitochondrial membranes (Stocco, 2000;Thomson, 1998;, apparently through a multiprotein complex associated to this organelle (Thomson, 2002) (Fig.10). …”

Section: Protein Phosphorylation In the Control Of Steroidogenesismentioning

confidence: 99%

The Role of Mitochondria in Syncytiotrophoblast Cells: Bioenergetics and Steroidogenesis

Martı́nez¹,

Milán²,

Flores-Herrera³

et al. 2012

Recent Advances in Research on the Human Placenta

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Evidence of undiscovered cell regulatory mechanisms: phosphoproteins and protein kinases in mitochondria

Cited by 79 publications

References 71 publications

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

Profiling Phosphoproteins of Yeast Mitochondria Reveals a Role of Phosphorylation in Assembly of the ATP Synthase

The Role of Mitochondria in Syncytiotrophoblast Cells: Bioenergetics and Steroidogenesis

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