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.

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

2020 ◽  
Author(s):  
Giulia Bertolin ◽  
Marie-Clotilde Alves-Guerra ◽  
Agnès Burel ◽  
Claude Prigent ◽  
Roland Le Borgne ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Aurora Kinase ◽  
Dependent Manner ◽  
Inner Mitochondrial Membrane ◽  
Serine Threonine Kinase ◽  
Independent Manner ◽  
Atp Production ◽  
Core Components

AbstractEpithelial 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. When overexpressed, AURKA induces the rupture of the Outer Mitochondrial Membrane in a proteasome-dependent manner. Then, AURKA triggers the degradation of Inner Mitochondrial Membrane (IMM)/matrix proteins by interacting with core components of the autophagy pathway. On the IMM, the kinase forms a tripartite complex with MAP1LC3 and the mitophagy receptor PHB2. This complex is necessary to trigger 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. This treatment also restores normal ATP production levels. Altogether, these data provide evidence for a previously undetected 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.

scholarly journals Mitochondrial dynamics: overview of molecular mechanisms

2018 ◽  
Vol 62 (3) ◽  
pp. 341-360 ◽  
Author(s):  
Lisa Tilokani ◽  
Shun Nagashima ◽  
Vincent Paupe ◽  
Julien Prudent
Keyword(s):  
Membrane Fusion ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Calcium Influx ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Membrane Lipid ◽  
Inner Mitochondrial Membrane ◽  
Step Process ◽  
Shape Distribution

Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control. Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases. These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria. It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites. Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission. Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx. Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1. In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes. Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects. This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals.

scholarly journals Alignment of sarcoplasmic reticulum-mitochondrial junctions with mitochondrial contact points

2011 ◽  
Vol 301 (5) ◽  
pp. H1907-H1915 ◽  
Author(s):  
Cecília García-Pérez ◽  
Timothy G. Schneider ◽  
György Hajnóczky ◽  
György Csordás
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Mitofusin 2 ◽  
Atp Production ◽  
Contact Points ◽  
Transmission Electron

Propagation of ryanodine receptor (RyR2)-derived Ca2+ signals to the mitochondrial matrix supports oxidative ATP production or facilitates mitochondrial apoptosis in cardiac muscle. Ca2+ transfer likely occurs locally at focal associations of the sarcoplasmic reticulum (SR) and mitochondria, which are secured by tethers. The outer mitochondrial membrane and inner mitochondrial membrane (OMM and IMM, respectively) also form tight focal contacts (contact points) that are enriched in voltage-dependent anion channels, the gates of OMM for Ca2+. Contact points could offer the shortest Ca2+ transfer route to the matrix; however, their alignment with the SR-OMM associations remains unclear. Here, in rat heart we have studied the distribution of mitochondria-associated SR in submitochondrial membrane fractions and evaluated the colocalization of SR-OMM associations with contact points using transmission electron microscopy. In a sucrose gradient designed for OMM purification, biochemical assays revealed lighter fractions enriched in OMM only and heavier fractions containing OMM, IMM, and SR markers. Pure OMM fractions were enriched in mitofusin 2, an ∼80 kDa mitochondrial fusion protein and SR-mitochondrial tether candidate, whereas in fractions of OMM + IMM + SR, a lighter (∼50 kDa) band detected by antibodies raised against the NH2 terminus of mitofusin 2 was dominating. Transmission electron microscopy revealed mandatory presence of contact points at the junctional SR-mitochondrial interface versus a random presence along matching SR-free OMM segments. For each SR-mitochondrial junction at least one tether was attached to contact points. These data establish the contact points as anchorage sites for the SR-mitochondrial physical coupling. Close coupling of the SR, OMM, and IMM is likely to provide a favorable spatial arrangement for local ryanodine receptor-mitochondrial Ca2+ signaling.

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 Mitochondrial respiratory chain inhibitors modulate the metal-induced inner mitochondrial membrane permeabilization.

2010 ◽  
Vol 57 (4) ◽  
Author(s):  
Elena A Belyaeva
Keyword(s):  
Heavy Metal ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Protective Action ◽  
Membrane Permeabilization ◽  
Mitochondrial Swelling ◽  
Complex Iii ◽  
Rat Liver Mitochondria ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Membrane Permeabilization

To elucidate the molecular mechanisms of the protective action of stigmatellin (an inhibitor of complex III of mitochondrial electron transport chain, mtETC) against the heavy metal-induced cytotoxicity, we tested its effectiveness against mitochondrial membrane permeabilization produced by heavy metal ions Cd²(+), Hg²(+), Cu²(+) and Zn²(+), as well as by Ca²(+) (in the presence of P(i)) or Se (in form of Na₂SeO₃) using isolated rat liver mitochondria. It was shown that stigmatellin modulated mitochondrial swelling produced by these metals/metalloids in the isotonic sucrose medium in the presence of ascorbate plus tetramethyl-p-phenylenediamine (complex IV substrates added for energization of the mitochondria). It was found that stigmatellin and other mtETC inhibitors enhanced the mitochondrial swelling induced by selenite. However, in the same medium, all the mtETC inhibitors tested as well as cyclosporin A and bongkrekic acid did not significantly affect Cu²(+)-induced swelling. In contrast, the high-amplitude swelling produced by Cd²(+), Hg²(+), Zn²(+), or Ca²(+) plus P(i) was significantly depressed by these inhibitors. Significant differences in the action of these metals/metalloids on the redox status of pyridine nucleotides, transmembrane potential and mitochondrial respiration were also observed. In the light of these results as well as the data from the recent literature, our hypothesis on a possible involvement of the respiratory supercomplex, formed by complex I (P-site) and complex III (S-site) in the mitochondrial permeabilization mediated by the mitochondrial transition pore, is updated.

scholarly journals Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane

2021 ◽  
Vol 11 ◽  
Author(s):  
Nantaporn Haskins ◽  
Shivaprasad Bhuvanendran ◽  
Claudio Anselmi ◽  
Anna Gams ◽  
Tomas Kanholm ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Urea Cycle ◽  
Super Resolution ◽  
Liver Mitochondria ◽  
Ammonia Toxicity ◽  
Mitochondrial Enzymes ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Acetylglutamate Synthase ◽  
Urea Cycle Enzymes

Mitochondrial enzymes involved in energy transformation are organized into multiprotein complexes that channel the reaction intermediates for efficient ATP production. Three of the mammalian urea cycle enzymes: N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase 1 (CPS1), and ornithine transcarbamylase (OTC) reside in the mitochondria. Urea cycle is required to convert ammonia into urea and protect the brain from ammonia toxicity. Urea cycle intermediates are tightly channeled in and out of mitochondria, indicating that efficient activity of these enzymes relies upon their coordinated interaction with each other, perhaps in a cluster. This view is supported by mutations in surface residues of the urea cycle proteins that impair ureagenesis in the patients, but do not affect protein stability or catalytic activity. We find the NAGS, CPS1, and OTC proteins in liver mitochondria can associate with the inner mitochondrial membrane (IMM) and can be co-immunoprecipitated. Our in-silico analysis of vertebrate NAGS proteins, the least abundant of the urea cycle enzymes, identified a protein-protein interaction region present only in the mammalian NAGS protein—“variable segment,” which mediates the interaction of NAGS with CPS1. Use of super resolution microscopy showed that NAGS, CPS1 and OTC are organized into clusters in the hepatocyte mitochondria. These results indicate that mitochondrial urea cycle proteins cluster, instead of functioning either independently or in a rigid multienzyme complex.

scholarly journals Mitochondrial Enzymes of the Urea Cycle Cluster at the Inner Mitochondrial Membrane

2020 ◽  
Author(s):  
Nantaporn Haskins ◽  
Shivaprasad Bhuvanendran ◽  
Anna Gams ◽  
Tomas Kanholm ◽  
Kristen M. Kocher ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Urea Cycle ◽  
Super Resolution ◽  
Liver Mitochondria ◽  
Ammonia Toxicity ◽  
Mitochondrial Enzymes ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Variable Segment ◽  
Urea Cycle Enzymes

AbstractMitochondrial enzymes involved in energy transformation are organized into multiprotein complexes that channel the reaction intermediates for efficient ATP production. Three of the mammalian urea cycle enzymes: N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase 1 (CPS1), and ornithine transcarbamylase (OTC) reside in the mitochondria. Urea cycle is required to convert ammonia into urea and protect the brain from ammonia toxicity. Urea cycle intermediates are tightly channeled in and out of mitochondria, indicating that efficient activity of these enzymes relies upon their coordinated interaction with each other perhaps in a multiprotein complex. This view is supported by mutations in surface residues of the urea cycle proteins that impair urea genesis in the patients but do not affect protein stability or catalytic activity. Further, we find one third of the NAGS, CPS1 and OTC proteins in liver mitochondria can associate with the inner mitochondrial membrane (IMM), and co-immunoprecipitate. Our in silico analysis of vertebrate NAGS proteins, the least abundant of the urea cycle enzymes, identified a region we call ‘variable segment’ present only in the mammalian NAGS protein. We experimentally confirmed that NAGS variable segment mediates the interaction of NAGS with CPS1. Use of Gated-Stimulation Emission Depletion (gSTED) super resolution microscopy showed that in situ, NAGS, CPS1 and OTC are organized into clusters. These results are consistent with mitochondrial urea cycle proteins forming a cluster instead of functioning either independently or in a rigid multienzyme complex.

scholarly journals Aurora kinase A localises to mitochondria to control organelle dynamics and energy production

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Giulia Bertolin ◽  
Anne-Laure Bulteau ◽  
Marie-Clotilde Alves-Guerra ◽  
Agnes Burel ◽  
Marie-Thérèse Lavault ◽  
...  
Keyword(s):  
Energy Production ◽  
Human Cancer ◽  
Mitochondrial Dynamics ◽  
Cancer Therapeutics ◽  
Aurora Kinase ◽  
Metabolic Reprogramming ◽  
Atp Production ◽  
Human Cancer Cell Lines ◽  
Epithelial Cancers ◽  
Mitochondrial Functions

Many epithelial cancers show cell cycle dysfunction tightly correlated with the overexpression of the serine/threonine kinase Aurora A (AURKA). Its role in mitotic progression has been extensively characterised, and evidence for new AURKA functions emerges. Here, we reveal that AURKA is located and imported in mitochondria in several human cancer cell lines. Mitochondrial AURKA impacts on two organelle functions: mitochondrial dynamics and energy production. When AURKA is expressed at endogenous levels during interphase, it induces mitochondrial fragmentation independently from RALA. Conversely, AURKA enhances mitochondrial fusion and ATP production when it is over-expressed. We demonstrate that AURKA directly regulates mitochondrial functions and that AURKA over-expression promotes metabolic reprogramming by increasing mitochondrial interconnectivity. Our work paves the way to anti-cancer therapeutics based on the simultaneous targeting of mitochondrial functions and AURKA inhibition.

scholarly journals Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 277
Author(s):  
Christina Wasmus ◽  
Jan Dudek
Keyword(s):  
Heart Failure ◽  
Respiratory Chain ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Mitochondrial Enzymes ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Functions ◽  
Metabolic Remodeling ◽  
Inherited Cardiomyopathies ◽  
The Impact

The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.

scholarly journals Cardiolipin, Non-Bilayer Structures and Mitochondrial Bioenergetics: Relevance to Cardiovascular Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1721
Author(s):  
Edward S. Gasanoff ◽  
Lev S. Yaguzhinsky ◽  
Győző Garab
Keyword(s):  
Electron Transport Chain ◽  
Mitochondrial Membrane ◽  
Mitochondrial Bioenergetics ◽  
Mitochondrial Membranes ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Functional Roles ◽  
Transport Chain ◽  
Energy Converting

The present review is an attempt to conceptualize a contemporary understanding about the roles that cardiolipin, a mitochondrial specific conical phospholipid, and non-bilayer structures, predominantly found in the inner mitochondrial membrane (IMM), play in mitochondrial bioenergetics. This review outlines the link between changes in mitochondrial cardiolipin concentration and changes in mitochondrial bioenergetics, including changes in the IMM curvature and surface area, cristae density and architecture, efficiency of electron transport chain (ETC), interaction of ETC proteins, oligomerization of respiratory complexes, and mitochondrial ATP production. A relationship between cardiolipin decline in IMM and mitochondrial dysfunction leading to various diseases, including cardiovascular diseases, is thoroughly presented. Particular attention is paid to the targeting of cardiolipin by Szeto–Schiller tetrapeptides, which leads to rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria. The role of cardiolipin in triggering non-bilayer structures and the functional roles of non-bilayer structures in energy-converting membranes are reviewed. The latest studies on non-bilayer structures induced by cobra venom peptides are examined in model and mitochondrial membranes, including studies on how non-bilayer structures modulate mitochondrial activities. A mechanism by which non-bilayer compartments are formed in the apex of cristae and by which non-bilayer compartments facilitate ATP synthase dimerization and ATP production is also presented.

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