Signaling at the gate: Phosphorylation of the mitochondrial protein import machinery

Rao, Satyawada Rama; Gerbeth, Carolin; Harbauer, Angelika B.; Mikropoulou, Despina; Meisinger, Chris; Schmidt, Oliver

doi:10.4161/cc.10.13.16054

Cited by 35 publications

(25 citation statements)

References 48 publications

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“…Recently, however, mass spectrometric analyses revealed that the subunits of the TOM complex are phosphorylated at multiple sites (Chi et al , 2007; Li et al , 2007; Albuquerque et al , 2008; Gnad et al , 2009; Schmidt et al , 2011). On the basis of prediction programs for kinase target sites and in vitro assays with recombinant Tom proteins and purified kinases, a number of candidate kinases for TOM phosphorylation were identified (Rao et al , 2011; Schmidt et al , 2011). So far, a functional role of TOM phosphorylation has been shown for the Tom receptors in vivo and in organello.…”

Section: Introductionmentioning

confidence: 99%

Biogenesis of the preprotein translocase of the outer mitochondrial membrane: protein kinase A phosphorylates the precursor of Tom40 and impairs its import

Rao

Schmidt

Harbauer

et al. 2012

MBoC

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The preprotein translocase of the outer mitochondrial membrane (TOM) functions as the main entry gate for the import of nuclear-encoded proteins into mitochondria. The major subunits of the TOM complex are the three receptors Tom20, Tom22, and Tom70 and the central channel-forming protein Tom40. Cytosolic kinases have been shown to regulate the biogenesis and activity of the Tom receptors. Casein kinase 2 stimulates the biogenesis of Tom22 and Tom20, whereas protein kinase A (PKA) impairs the receptor function of Tom70. Here we report that PKA exerts an inhibitory effect on the biogenesis of the β-barrel protein Tom40. Tom40 is synthesized as precursor on cytosolic ribosomes and subsequently imported into mitochondria. We show that PKA phosphorylates the precursor of Tom40. The phosphorylated Tom40 precursor is impaired in import into mitochondria, whereas the nonphosphorylated precursor is efficiently imported. We conclude that PKA plays a dual role in the regulation of the TOM complex. Phosphorylation by PKA not only impairs the receptor activity of Tom70, but it also inhibits the biogenesis of the channel protein Tom40.

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Section: Introductionmentioning

confidence: 99%

Biogenesis of the preprotein translocase of the outer mitochondrial membrane: protein kinase A phosphorylates the precursor of Tom40 and impairs its import

Rao

Schmidt

Harbauer

et al. 2012

MBoC

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“…61 It is thus possible that defects in mitochondrial protein import due to degradation of TOM complex components contribute to the mitochondrial dysfunction observed in senescent cells. It is known that the TOM complex is regulated by phosphorylation, 75 and we found phosphorylation of serine 91 of TOMM70A and serine 186 of TOMM34 in Ras-induced senescence. It will be of considerable interest to address whether these sites are phosphorylated by the ERKs or other kinases and mediate recognition of E3 ligases.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 90%

Cellular senescence and protein degradation

et al. 2014

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Autophagy and the ubiquitin-proteasome pathway (UPP) are the major protein degradation systems in eukaryotic cells. Whereas the former mediate a bulk nonspecific degradation, the UPP allows a rapid degradation of specific proteins. Both systems have been shown to play a role in tumorigenesis, and the interest in developing therapeutic agents inhibiting protein degradation is steadily growing. However, emerging data point to a critical role for autophagy in cellular senescence, an established tumor suppressor mechanism. Recently, a selective protein degradation process mediated by the UPP was also shown to contribute to the senescence phenotype. This process is tightly regulated by E3 ubiquitin ligases, deubiquitinases, and several post-translational modifications of target proteins. Illustrating the complexity of UPP, more than 600 human genes have been shown to encode E3 ubiquitin ligases, a number which exceeds that of the protein kinases. Nevertheless, our knowledge of proteasome-dependent protein degradation as a regulated process in cellular contexts such as cancer and senescence remains very limited. Here we discuss the implications of protein degradation in senescence and attempt to relate this function to the protein degradation pattern observed in cancer cells.

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“…The interaction of the preprotein-loaded chaperone with the OM receptors exhibits some specificity, but an overlap in the function of one of the OM receptors has been reported [24]. In a very interesting set of recent studies it has been shown that the TOM complex is regulated by phosphorylation events performed by the cytosolic kinases, CK2 and kinase A [24], [25], [26], [27]. Additionally, Tom40 itself has a binding region for precursors allowing it to function independently from the receptors for targeting to the mitochondrial matrix [28], [29].…”

Section: Import Pathwaysmentioning

confidence: 99%

Oxidative folding in the mitochondrial intermembrane space: A regulated process important for cell physiology and disease

Chatzi

Manganas

Tokatlidis

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Mitochondria are fundamental organelles with a complex internal architecture that fulfill important diverse functions including iron–sulfur cluster assembly and cell respiration. Intense work for more than 30 years has identified the key protein import components and the pathways involved in protein targeting and assembly. More recently, oxidative folding has been discovered as one important mechanism for mitochondrial proteostasis whilst several human disorders have been linked to this pathway. We describe the molecular components of this pathway in view of their putative redox regulation and we summarize available evidence on the connections of these pathways to human disorders.

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Signaling at the gate: Phosphorylation of the mitochondrial protein import machinery

Cited by 35 publications

References 48 publications

Biogenesis of the preprotein translocase of the outer mitochondrial membrane: protein kinase A phosphorylates the precursor of Tom40 and impairs its import

Biogenesis of the preprotein translocase of the outer mitochondrial membrane: protein kinase A phosphorylates the precursor of Tom40 and impairs its import

Cellular senescence and protein degradation

Oxidative folding in the mitochondrial intermembrane space: A regulated process important for cell physiology and disease

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