scholarly journals PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy

2016 ◽  
Vol 213 (2) ◽  
pp. 163-171 ◽  
Author(s):  
Kenneth R. Pryde ◽  
Heather L. Smith ◽  
Kai-Yin Chau ◽  
Anthony H.V. Schapira
Keyword(s):  
Protein Kinase ◽  
Parkinson Disease ◽  
Protein Kinase A ◽  
Mitochondrial Membrane ◽  
Mitochondrial Fission ◽  
Scaffold Protein ◽  
Outer Mitochondrial Membrane ◽  
Related Protein ◽  
Anchoring Protein ◽  
Kinase A

Mitochondrial fission is essential for the degradation of damaged mitochondria. It is currently unknown how the dynamin-related protein 1 (DRP1)–associated fission machinery is selectively targeted to segregate damaged mitochondria. We show that PTEN-induced putative kinase (PINK1) serves as a pro-fission signal, independently of Parkin. Normally, the scaffold protein AKAP1 recruits protein kinase A (PKA) to the outer mitochondrial membrane to phospho-inhibit DRP1. We reveal that after damage, PINK1 triggers PKA displacement from A-kinase anchoring protein 1. By ejecting PKA, PINK1 ensures the requisite fission of damaged mitochondria for organelle degradation. We propose that PINK1 functions as a master mitophagy regulator by activating Parkin and DRP1 in response to damage. We confirm that PINK1 mutations causing Parkinson disease interfere with the orchestration of selective fission and mitophagy by PINK1.

scholarly journals The phosphorylation status of Ser-637 in dynamin-related protein 1 (Drp1) does not determine Drp1 recruitment to mitochondria

2019 ◽  
Vol 294 (46) ◽  
pp. 17262-17277 ◽  
Author(s):  
Rong Yu ◽  
Tong Liu ◽  
Chenfei Ning ◽  
Fei Tan ◽  
Shao-Bo Jin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Mitochondrial Fission ◽  
Elongation Factor ◽  
Subcellular Fractionation ◽  
Related Protein ◽  
Wild Type ◽  
Mitochondrial Elongation ◽  
Elongation Factor 1 ◽  
Kinase A

Recruitment of the GTPase dynamin-related protein 1 (Drp1) to mitochondria is a central step required for mitochondrial fission. Reversible Drp1 phosphorylation has been implicated in the regulation of this process, but whether Drp1 phosphorylation at Ser-637 determines its subcellular localization and fission activity remains to be fully elucidated. Here, using HEK 293T cells and immunofluorescence, immunoblotting, RNAi, subcellular fractionation, co-immunoprecipitation assays, and CRISPR/Cas9 genome editing, we show that Drp1 phosphorylated at Ser-637 (Drp1pS637) resides both in the cytosol and on mitochondria. We found that the receptors mitochondrial fission factor (Mff) and mitochondrial elongation factor 1/2 (MIEF1/2) interact with and recruit Drp1pS637 to mitochondria and that elevated Mff or MIEF levels promote Drp1pS637 accumulation on mitochondria. We also noted that protein kinase A (PKA), which mediates phosphorylation of Drp1 on Ser-637, is partially present on mitochondria and interacts with both MIEFs and Mff. PKA knockdown did not affect the Drp1-Mff interaction, but slightly enhanced the interaction between Drp1 and MIEFs. In Drp1-deficient HEK 293T cells, both phosphomimetic Drp1-S637D and phospho-deficient Drp1-S637A variants, like wild-type Drp1, located to the cytosol and to mitochondria and rescued a Drp1 deficiency-induced mitochondrial hyperfusion phenotype. However, Drp1-S637D was less efficient than Drp1-WT and Drp1-S637A in inducing mitochondrial fission. In conclusion, the Ser-637 phosphorylation status in Drp1 is not a determinant that controls Drp1 recruitment to mitochondria.

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

2012 ◽  
Vol 23 (9) ◽  
pp. 1618-1627 ◽  
Author(s):  
Sanjana Rao ◽  
Oliver Schmidt ◽  
Angelika B. Harbauer ◽  
Birgit Schönfisch ◽  
Bernard Guiard ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Mitochondrial Membrane ◽  
Inhibitory Effect ◽  
Outer Mitochondrial Membrane ◽  
Central Channel ◽  
Receptor Function ◽  
Tom Complex ◽  
Mitochondrial Membrane Protein ◽  
Kinase A

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.

scholarly journals Depletion of dAKAP1–protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility

2018 ◽  
Vol 294 (9) ◽  
pp. 3152-3168 ◽  
Author(s):  
Stacey Aggarwal ◽  
Laura Gabrovsek ◽  
Lorene K. Langeberg ◽  
Martin Golkowski ◽  
Shao-En Ong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Mitochondrial Membrane ◽  
Cell Metabolism ◽  
Outer Mitochondrial Membrane ◽  
Cancer Cell Metabolism ◽  
Kinase A

scholarly journals Protein Kinase A-induced tamoxifen resistance is mediated by anchoring protein AKAP13

BMC Cancer ◽  
2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Cristiane Bentin Toaldo ◽  
Xanthippi Alexi ◽  
Karin Beelen ◽  
Marleen Kok ◽  
Michael Hauptmann ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Tamoxifen Resistance ◽  
Anchoring Protein ◽  
Kinase A

β-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling

2009 ◽  
Vol 33 (3) ◽  
pp. 519-529 ◽  
Author(s):  
Elzbieta Luchowska ◽  
Renata Kloc ◽  
Bartosz Olajossy ◽  
Sebastian Wnuk ◽  
Marian Wielosz ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Acid Production ◽  
Kynurenic Acid ◽  
Related Protein ◽  
Kinase A

scholarly journals Radial Spoke Protein 3 Is a Mammalian Protein Kinase A-anchoring Protein That Binds ERK1/2

2009 ◽  
Vol 284 (43) ◽  
pp. 29437-29445 ◽  
Author(s):  
Arif Jivan ◽  
Svetlana Earnest ◽  
Yu-Chi Juang ◽  
Melanie H. Cobb
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Radial Spoke ◽  
Anchoring Protein ◽  
Mammalian Protein ◽  
Kinase A
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