PINK1 activation–turning on a promiscuous kinase

2015 ◽  
Vol 43 (2) ◽  
pp. 280-286 ◽  
Author(s):  
Liesbeth Aerts ◽  
Bart De Strooper ◽  
Vanessa A. Morais
Keyword(s):  
Mitochondrial Dynamics ◽  
Proteolytic Processing ◽  
Serine Threonine Kinase ◽  
Post Translational Modifications ◽  
Atp Production ◽  
Threonine Kinase ◽  
Health And Disease ◽  
And Function ◽  
Phosphatase And Tensin Homologue ◽  
Production Stress

PINK1 [phosphatase and tensin homologue (PTEN)-induced putative kinase 1] is a serine/threonine kinase targeted to mitochondria and implicated in early-onset recessive Parkinson's disease (PD). Through the phosphorylation of its downstream targets, PINK1 regulates multiple mitochondrial processes, including ATP production, stress-response and mitochondrial dynamics and quality control. The orchestration of such a wide array of functions by an individual kinase requires a fine-tuned and versatile regulation of its activity. PINK1 proteolytic processing, trafficking and localization, as well as different post-translational modifications, affect its activity and function. Unravelling the regulatory mechanisms of PINK1 is essential for a full comprehension of its kinase function in health and disease.

The endoplasmic reticulum/mitochondria interface: a subcellular platform for the orchestration of the functions of the PINK1–Parkin pathway?

2015 ◽  
Vol 43 (2) ◽  
pp. 297-301 ◽  
Author(s):  
Zoi Erpapazoglou ◽  
Olga Corti
Keyword(s):  
Endoplasmic Reticulum ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Serine Threonine Kinase ◽  
Subcellular Compartment ◽  
Ubiquitin Protein Ligase ◽  
Threonine Kinase ◽  
Parkinsonian Syndromes ◽  
Phosphatase And Tensin Homologue ◽  
Familial Parkinson’S Disease

Mitochondrial dysfunction is a hallmark of both idiopathic and familial Parkinson's disease (PD). Mutations in the PARK2 and PARK6 genes, coding for the cytosolic E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1 [phosphatase and tensin homologue (PTEN)-induced putative kinase 1], lead to clinically similar early-onset Parkinsonian syndromes. PINK1 and Parkin cooperate within a conserved pathway to preserve mitochondrial quality through the regulation of a variety of processes, including mitochondrial dynamics, transport, bioenergetics, biogenesis and turnover. The molecular mechanisms behind the orchestration of this plethora of functions remain poorly understood. In the present review, we emphasize the functional overlap between the PINK1–Parkin pathway and the endoplasmic reticulum (ER)-mitochondria interface, a subcellular compartment critically involved in neurodegeneration. We discuss how this compartment may constitute a hub for the spatiotemporal organization of the activities of the PINK1–Parkin pathway.

scholarly journals Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

Oncogene ◽  
2021 ◽  
Author(s):  
Rósula García-Navas ◽  
Pilar Liceras-Boillos ◽  
Carmela Gómez ◽  
Fernando C. Baltanás ◽  
Nuria Calzada ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Redox Homeostasis ◽  
Atp Production ◽  
Oxidative Energy Metabolism ◽  
Ras Activation ◽  
Mitochondrial Defects ◽  
Critical Requirement ◽  
Dynamics And Function ◽  
And Function ◽  
And Control

AbstractSOS1 ablation causes specific defective phenotypes in MEFs including increased levels of intracellular ROS. We showed that the mitochondria-targeted antioxidant MitoTEMPO restores normal endogenous ROS levels, suggesting predominant involvement of mitochondria in generation of this defective SOS1-dependent phenotype. The absence of SOS1 caused specific alterations of mitochondrial shape, mass, and dynamics accompanied by higher percentage of dysfunctional mitochondria and lower rates of electron transport in comparison to WT or SOS2-KO counterparts. SOS1-deficient MEFs also exhibited specific alterations of respiratory complexes and their assembly into mitochondrial supercomplexes and consistently reduced rates of respiration, glycolysis, and ATP production, together with distinctive patterns of substrate preference for oxidative energy metabolism and dependence on glucose for survival. RASless cells showed defective respiratory/metabolic phenotypes reminiscent of those of SOS1-deficient MEFs, suggesting that the mitochondrial defects of these cells are mechanistically linked to the absence of SOS1-GEF activity on cellular RAS targets. Our observations provide a direct mechanistic link between SOS1 and control of cellular oxidative stress and suggest that SOS1-mediated RAS activation is required for correct mitochondrial dynamics and function.

scholarly journals Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1493-1502 ◽  
Author(s):  
Mondira Kundu ◽  
Tullia Lindsten ◽  
Chia-Ying Yang ◽  
Junmin Wu ◽  
Fangping Zhao ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Critical Role ◽  
Serine Threonine Kinase ◽  
Newborn Mice ◽  
Atp Production ◽  
Threonine Kinase ◽  
Selective Elimination ◽  
Reticulocyte Maturation ◽  
Erythroid Maturation

Abstract Production of a red blood cell's hemoglobin depends on mitochondrial heme synthesis. However, mature red blood cells are devoid of mitochondria and rely on glycolysis for ATP production. The molecular basis for the selective elimination of mitochondria from mature red blood cells remains controversial. Recent evidence suggests that clearance of both mitochondria and ribosomes, which occurs in reticulocytes following nuclear extrusion, depends on autophagy. Here, we demonstrate that Ulk1, a serine threonine kinase with homology to yeast atg1p, is a critical regulator of mitochondrial and ribosomal clearance during the final stages of erythroid maturation. However, in contrast to the core autophagy genes such as atg5 and atg7, expression of ulk1 is not essential for induction of macroautophagy in response to nutrient deprivation or for survival of newborn mice. Together, these data suggest that the ATG1 homologue, Ulk1, is a component of the selective autophagy machinery that leads to the elimination of organelles in erythroid cells rather that an essential mechanistic component of autophagy.

scholarly journals Target of Rapamycin in Control of Autophagy: Puppet Master and Signal Integrator

2020 ◽  
Vol 21 (21) ◽  
pp. 8259
Author(s):  
Yosia Mugume ◽  
Zakayo Kazibwe ◽  
Diane C. Bassham
Keyword(s):  
Degradation Pathway ◽  
Target Of Rapamycin ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Photosynthetic Organisms ◽  
Downstream Effectors ◽  
Evolutionarily Conserved ◽  
Recent Developments ◽  
Stress Signals ◽  
And Function

The target of rapamycin (TOR) is an evolutionarily-conserved serine/threonine kinase that senses and integrates signals from the environment to coordinate developmental and metabolic processes. TOR senses nutrients, hormones, metabolites, and stress signals to promote cell and organ growth when conditions are favorable. However, TOR is inhibited when conditions are unfavorable, promoting catabolic processes such as autophagy. Autophagy is a macromolecular degradation pathway by which cells degrade and recycle cytoplasmic materials. TOR negatively regulates autophagy through phosphorylation of ATG13, preventing activation of the autophagy-initiating ATG1-ATG13 kinase complex. Here we review TOR complex composition and function in photosynthetic and non-photosynthetic organisms. We also review recent developments in the identification of upstream TOR activators and downstream effectors of TOR. Finally, we discuss recent developments in our understanding of the regulation of autophagy by TOR in photosynthetic organisms.

scholarly journals Tyr198 is the Essential Autophosphorylation Site for STK16 Localization and Kinase Activity

2019 ◽  
Vol 20 (19) ◽  
pp. 4852 ◽  
Author(s):  
Junjun Wang ◽  
Juanjuan Liu ◽  
Xinmiao Ji ◽  
Xin Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Kinase Domain ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Activation Segment ◽  
And Function

STK16, reported as a Golgi localized serine/threonine kinase, has been shown to participate in multiple cellular processes, including the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. However, the mechanisms of the regulation of its kinase activity remain underexplored. It was known that STK16 is autophosphorylated at Thr185, Ser197, and Tyr198 of the activation segment in its kinase domain. We found that STK16 localizes to the cell membrane and the Golgi throughout the cell cycle, but mutations in the auto-phosphorylation sites not only alter its subcellular localization but also affect its kinase activity. In particular, the Tyr198 mutation alone significantly reduced the kinase activity of STK16, abolished its Golgi and membrane localization, and affected the cell cycle progression. This study demonstrates that a single site autophosphorylation of STK16 could affect its localization and function, which provides insights into the molecular regulatory mechanism of STK16’s kinase activity.

Fas-activated serine/threonine kinase: Structure and function

Gene Reports ◽  
2017 ◽  
Vol 8 ◽  
pp. 117-127 ◽  
Author(s):  
Saurabha Srivastava ◽  
Sunayana Begum Syed ◽  
Vijay Kumar ◽  
Asimul Islam ◽  
Faizan Ahmad ◽  
...  
Keyword(s):  
Structure And Function ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
And Function ◽  
Kinase Structure

scholarly journals Dependence of Leydig Cell’s Mitochondrial Physiology on Luteinizing Hormone Signaling

Life ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 19
Author(s):  
Marija L. J. Medar ◽  
Dijana Z. Marinkovic ◽  
Zvezdana Kojic ◽  
Alisa P. Becin ◽  
Isidora M. Starovlah ◽  
...  
Keyword(s):  
Leydig Cells ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
Experimental Models ◽  
Atp Production ◽  
Transmission Electron ◽  
Important Regulator ◽  
Steroidogenic Cells ◽  
And Function

Knowledge about the relationship between steroidogenesis and the regulation of the mitochondrial bioenergetics and dynamics, in steroidogenic cells, is not completely elucidated. Here we employed in vivo and ex vivo experimental models to analyze mitochondrial physiology in Leydig cells depending on the different LH-cAMP environments. Activation of LH-receptor in rat Leydig cells ex and in vivo triggered cAMP, increased oxygen consumption, mitoenergetic and steroidogenic activities. Increased mitoenergetic activity i.e., ATP production is achieved through augmented glycolytic ATP production and a small part of oxidative phosphorylation (OXPHOS). Transcription of major genes responsible for mitochondrial dynamics was upregulated for Ppargc1a (regulator of mitogenesis and function) and downregulated for Drp1 (main fission marker), Prkn, Pink1 and Tfeb (mitophagy markers). Leydig cells from gonadotropin-treated rats show increased mitogenesis confirmed by increased mitochondrial mass, increased mtDNA, more frequent mitochondria observed by a transmission electron microscope and increased expression of subunits of respiratory proteins Cytc/CYTC and COX4. Opposite, Leydig cells from hypogonadotropic-hypogonadal rats characterized by low LH-cAMP, testosterone, and ATP production, reduced markers of mitogenesis and mitofusion (Mfn1/2, Opa1) associated with reduced mtDNA content. Altogether results underline LH-cAMP signaling as an important regulator of mitochondrial physiology arranging mitochondrial dynamics, bioenergetic and steroidogenic function in Leydig cells.

scholarly journals Light limitation inducing overcompensatory growth of cyanobacteria and function of serine/threonine kinase (STK) genes involved

2021 ◽  
Author(s):  
Wei Dai ◽  
Xiangdong Bi ◽  
Huairong Zhong ◽  
Xueying Wang ◽  
Shaojie Dong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Light Intensity ◽  
Cyanobacterial Blooms ◽  
Light Limitation ◽  
Wild Type ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Genes Expression ◽  
And Function ◽  
Intensity Expression

Abstract The rapid overcompensatory growth that appears when cyanobacteria are supplied with adequate resources after a period of resource deprivation might contribute to the occurrence of cyanobacterial blooms. We investigated the changing characteristics of overcompensatory growth and serine/threonine kinase (STK) genes expression of cyanobacterium Microcystis aeruginosa in response to light limitation. The results showed M. aeruginosa exhibited overcompensatory growth for two days after light recovery, during which the increase in growth was inversely related to light intensity. Expression of STK genes, such as spkD, was upregulated significantly at 0.5–4 h after light recovery (P < 0.05). To investigate the function of STK genes in the overcompensatory growth, M. aeruginosa spkD was heterologously expressed in Synechocystis. Transgenic Synechocystis exhibited greater and longer overcompensatory growth than wild-type Synechocystis after light recovery. Relative expression levels of STK genes in transgenic Synechocystis were significantly higher than those in wild-type Synechocystis at 24 h of light recovery (P < 0.05). Heterologous expression of Microcystis spkD might stimulate overcompensatory growth of Synechocystis via affecting its STK gene expression.

scholarly journals Connexins: Synthesis, Post-Translational Modifications and Trafficking in Health and Disease

2018 ◽  
Author(s):  
Trond Aasen ◽  
Scott Johnstone ◽  
Laia Vidal-Brime ◽  
K. Sabrina Lynn ◽  
Michael Koval
Keyword(s):  
Intercellular Communication ◽  
Protein Level ◽  
Transmembrane Proteins ◽  
Transcriptional Level ◽  
Critical Feature ◽  
Post Translational Modifications ◽  
Connexin Gene ◽  
Independent Functions ◽  
Health And Disease ◽  
And Function

Connexins are tetraspan transmembrane proteins that form gap junctions and facilitate direct intercellular communication, a critical feature for the development, function and homeostasis of tissues and organs. In addition, a growing number of gap junction-independent functions are being ascribed to these proteins. The connexin gene family is under extensive regulation at the transcriptional and post-transcriptional level, and undergoes numerous modifications at the protein level, including phosphorylation, which ultimately affects their trafficking, stability and function. Here, we summarize these key regulatory events, with emphasis on how these affect their multi-functionality in health and disease.

scholarly journals Mitochondrial Aurora kinase A induces mitophagy by interacting with MAP1LC3 and Prohibitin 2

2021 ◽  
Vol 4 (6) ◽  
pp. e202000806
Author(s):  
Giulia Bertolin ◽  
Marie-Clotilde Alves-Guerra ◽  
Angélique Cheron ◽  
Agnès Burel ◽  
Claude Prigent ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Aurora Kinase ◽  
Inner Mitochondrial Membrane ◽  
Serine Threonine Kinase ◽  
Independent Manner ◽  
Atp Production ◽  
Core Components ◽  
Autophagy Pathway

Epithelial and haematologic tumours often show the overexpression of the serine/threonine kinase AURKA. Recently, AURKA was shown to localise at mitochondria, where it regulates mitochondrial dynamics and ATP production. Here we define the molecular mechanisms of AURKA in regulating mitochondrial turnover by mitophagy. AURKA triggers the degradation of Inner Mitochondrial Membrane/matrix proteins by interacting with core components of the autophagy pathway. On the inner mitochondrial membrane, the kinase forms a tripartite complex with MAP1LC3 and the mitophagy receptor PHB2, which triggers mitophagy in a PARK2/Parkin–independent manner. The formation of the tripartite complex is induced by the phosphorylation of PHB2 on Ser39, which is required for MAP1LC3 to interact with PHB2. Last, treatment with the PHB2 ligand xanthohumol blocks AURKA-induced mitophagy by destabilising the tripartite complex and restores normal ATP production levels. Altogether, these data provide evidence for a role of AURKA in promoting mitophagy through the interaction with PHB2 and MAP1LC3. This work paves the way to the use of function-specific pharmacological inhibitors to counteract the effects of the overexpression of AURKA in cancer.

Sign in / Sign up

Export Citation Format

Share Document