The Experts below are selected from a list of 1125 Experts worldwide ranked by ideXlab platform
Luca Scorrano - One of the best experts on this subject based on the ideXlab platform.
-
Neutrophil extracellular trap formation requires OPA1-dependent glycolytic ATP production
Nature Communications, 2018Co-Authors: Poorya Amini, Darko Stojkov, Andrea Felser, Christopher B. Jackson, Carolina Courage, André Schaller, Laurent Gelman, Maria Eugenia Soriano, Jean-marc Nuoffer, Luca ScorranoAbstract:Optic Atrophy 1 (OPA1) is a mitochondrial inner membrane protein that has an important role in mitochondrial fusion and structural integrity. Dysfunctional OPA1 mutations cause Atrophy of the Optic nerve leading to blindness. Here, we show that OPA1 has an important role in the innate immune system. Using conditional knockout mice lacking Opa1 in neutrophils (Opa1N∆), we report that lack of OPA1 reduces the activity of mitochondrial electron transport complex I in neutrophils. This then causes a decline in adenosine-triphosphate (ATP) production through glycolysis due to lowered NAD+ availability. Additionally, we show that OPA1-dependent ATP production in these cells is required for microtubule network assembly and for the formation of neutrophil extracellular traps. Finally, we show that Opa1N∆ mice exhibit a reduced antibacterial defense capability against Pseudomonas aeruginosa.
-
Keeping mitochondria in shape: A matter of life and death
Free Radical Biology and Medicine, 2018Co-Authors: Luca ScorranoAbstract:Mitochondrial morphology changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Today we will discuss our recent in vitro and in vivo results that place the inner mitochondrial membrane shaping protein Optic Atrophy 1 (OPA1) at the crossroad between oxidative tissue damage, intermediate metabolism and angiogenesis, the physiological process through which new blood vessels form from pre-existing ones.
-
Reduction of endoplasmic reticulum stress attenuates the defects caused by Drosophila mitofusin depletion
Journal of Cell Biology, 2014Co-Authors: Valentina Debattisti, Diana Pendin, Elena Ziviani, Andrea Daga, Luca ScorranoAbstract:Ablation of the mitochondrial fusion and endoplasmic reticulum (ER)–tethering protein Mfn2 causes ER stress, but whether this is just an epiphenomenon of mitochondrial dysfunction or a contributor to the phenotypes in mitofusin (Mfn)-depleted Drosophila melanogaster is unclear. In this paper, we show that reduction of ER dysfunction ameliorates the functional and developmental defects of flies lacking the single Mfn mitochondrial assembly regulatory factor (Marf). Ubiquitous or neuron- and muscle-specific Marf ablation was lethal, altering mitochondrial and ER morphology and triggering ER stress that was conversely absent in flies lacking the fusion protein Optic Atrophy 1. Expression of Mfn2 and ER stress reduction in flies lacking Marf corrected ER shape, attenuating the developmental and motor defects. Thus, ER stress is a targetable pathogenetic component of the phenotypes caused by Drosophila Mfn ablation.
-
Loss of Prohibitin Induces Mitochondrial Damages Altering β-Cell Function and Survival and Is Responsible for Gradual Diabetes Development
Diabetes, 2013Co-Authors: Sachin Supale, Luca Scorrano, Carsten Merkwirth, Fabrizio Thorel, Asllan Gjinovci, Pedro Luis Herrera, Paolo Meda, Thomas Langer, Pierre MaechlerAbstract:Prohibitins are highly conserved proteins mainly implicated in the maintenance of mitochondrial function and architecture. Their dysfunctions are associated with aging, cancer, obesity, and inflammation. However, their possible role in pancreatic β-cells remains unknown. The current study documents the expression of prohibitins in human and rodent islets and their key role for β-cell function and survival. Ablation of Phb2 in mouse β-cells sequentially resulted in impairment of mitochondrial function and insulin secretion, loss of β-cells, progressive alteration of glucose homeostasis, and, ultimately, severe diabetes. Remarkably, these events progressed over a 3-week period of time after weaning. Defective insulin supply in β-Phb2−/− mice was contributed by both β-cell dysfunction and apoptosis, temporarily compensated by increased β-cell proliferation. At the molecular level, we observed that deletion of Phb2 caused mitochondrial abnormalities, including reduction of mitochondrial DNA copy number and respiratory chain complex IV levels, altered mitochondrial activity, cleavage of L-Optic Atrophy 1, and mitochondrial fragmentation. Overall, our data demonstrate that Phb2 is essential for metabolic activation of mitochondria and, as a consequence, for function and survival of β-cells.
-
OPA1 promotes pH flashes that spread between contiguous mitochondria without matrix protein exchange
The EMBO Journal, 2013Co-Authors: Jaime Santo-domingo, Luca Scorrano, Marta Giacomello, Damon Poburko, Nicolas DemaurexAbstract:The chemical nature and functional significance of mitochondrial flashes associated with fluctuations in mitochondrial membrane potential is unclear. Using a ratiometric pH probe insensitive to superoxide, we show that flashes reflect matrix alkalinization transients of ∼0.4 pH units that persist in cells permeabilized in ion-free solutions and can be evoked by imposed mitochondrial depolarization. Ablation of the pro-fusion protein Optic Atrophy 1 specifically abrogated pH flashes and reduced the propagation of matrix photoactivated GFP (paGFP). Ablation or invalidation of the pro-fission Dynamin-related protein 1 greatly enhanced flash propagation between contiguous mitochondria but marginally increased paGFP matrix diffusion, indicating that flashes propagate without matrix content exchange. The pH flashes were associated with synchronous depolarization and hyperpolarization events that promoted the membrane potential equilibration of juxtaposed mitochondria. We propose that flashes are energy conservation events triggered by the opening of a fusion pore between two contiguous mitochondria of different membrane potentials, propagating without matrix fusion to equilibrate the energetic state of connected mitochondria.
Dale E Abel - One of the best experts on this subject based on the ideXlab platform.
-
1984 p Optic Atrophy 1 deletion in brown adipose tissue induces browning of white fat by inducing fgf 21
Diabetes, 2019Co-Authors: Renata Pereira Alambert, Satya M Tadinada, Dale E AbelAbstract:Optic Atrophy 1 (OPA1) is a mitochondrial inner membrane protein that regulates inner mitochondrial membrane fusion, cristae structure and respiratory capacity. Mitochondria are critical for the thermogenic activation of brown adipocytes. However, the role of OPA1 and mitochondrial dynamics in brown adipose tissue (BAT) physiology and in systemic metabolism is incompletely understood. We generated mice lacking OPA1 specifically in BAT by crossing mice floxed for the Opa1 genewith mice harboring the Cre recombinase under the control of the Ucp1promoter (OPA1 BAT-KO). Although mitochondrial respiratory capacity was reduced in mitochondria isolated from BAT of OPA1 BAT-KO, mitochondria respirations were elevated in the inguinal fat pad of these mice, which correlated with increased UCP1 protein levels and induction of thermogenic genes, consistent with browning of white adipose tissue (WAT). OPA1 BAT-KO mice also had elevated energy expenditure and reduced WAT mass. We, then, hypothesized that a BAT-derived secreted factor, or batokine, mediated these systemic effects. Upon mRNA expression analysis of a panel of batokines in OPA1-BAT KO mice, we found Fibroblast Growth Factor 21 (FGF-21) to be significantly elevated in BAT. We, therefore, generated OPA1/FGF-21 BAT-DKO mice. DKO mice had normalized WAT mass and lacked the induction of thermogenic genes in WAT. In conclusion, OPA1 deletion in BAT results in increased FGF-21 expression, which induces browning of WAT to increase energy expenditure and promote leanness. Disclosure R. Pereira Alambert: None. S. Tadinada: None. E. Abel: None. Funding American Heart Association
-
abstract 12196 Optic Atrophy 1 deficiency in skeletal muscle results in progressive mitochondrial dysfunction but prevents age induced obesity and glucose intolerance
Circulation, 2014Co-Authors: Renata Pereira, Zhonggang Li, Karen Oliveira, Karla Maria Pereira Pires, Dale E AbelAbstract:Mitochondrial dysfunction develops in skeletal muscle with aging and may contribute to insulin resistance, which increases cardiovascular risk. A link between skeletal muscle insulin resistance and perturbed mitochondrial fusion and fission has been suggested but not proven. Optic Atrophy 1 (OPA1) is an inner mitochondrial membrane protein that plays a fundamental role in mitochondrial fusion, quality control and respiratory function. OPA1 levels are reduced in muscle from elderly subjects; however, the specific roles of OPA1 in the aging muscle have not been studied. We, therefore, generated a mouse model with inducible deletion of the OPA1 gene in skeletal muscle of adult C57Bl6 mice, by crossing OPA1 floxed mice with HSA-Cre (ERT2) mice (KO). Four-week-old KO and wild-type (WT) mice were treated with tamoxifen for 5 days to induce recombination, resulting in a 60% reduction in OPA1 protein levels 8 weeks after treatment (12-wk-old mice). OPA1 deficiency resulted in altered mitochondrial cristae morphol...
Yisang Yoon - One of the best experts on this subject based on the ideXlab platform.
-
the short variant of Optic Atrophy 1 opa1 improves cell survival under oxidative stress
Journal of Biological Chemistry, 2020Co-Authors: Sylvia B Smith, Sheyshing Sheu, Yisang YoonAbstract:Optic Atrophy 1 (OPA1) is a dynamin protein that mediates mitochondrial fusion at the inner membrane. OPA1 is also necessary for maintaining the cristae, and thus essential for supporting cellular energetics. OPA1 exists as membrane-anchored long form (L-OPA1) and short form (S-OPA1) that lacks the transmembrane region and is generated by cleavage of L-OPA1. Mitochondrial dysfunction and cellular stresses activate the inner membrane-associated zinc metallopeptidase OMA1 that cleaves L-OPA1, causing S-OPA1 accumulation. The prevailing notion has been that L-OPA1 is the functional form while S-OPA1 is an inactive cleavage product in mammals, and that stress-induced OPA1 cleavage causes mitochondrial fragmentation and sensitizes cells to death. However, S-OPA1 contains all functional domains of dynamin proteins, suggesting that it has a physiological role. Indeed, we recently demonstrated that S-OPA1 can maintain cristae and energetics through its GTPase activity, despite lacking fusion activity. Here, applying oxidant insult that induces OPA1 cleavage, we show that cells unable to generate S-OPA1 are more sensitive to this stress under obligatory respiratory conditions, leading to necrotic death. These findings indicate that L-OPA1 and S-OPA1 differ in maintaining mitochondrial function. Mechanistically, we found that cells that exclusively express L-OPA1 generate more superoxide and are more sensitive to Ca2+-induced mitochondrial permeability transition, suggesting that S-OPA1, and not L-OPA1, protects against cellular stress. Importantly, silencing of OMA1 expression increased oxidant-induced cell death, indicating that stress-induced OPA1 cleavage supports cell survival. Our findings suggest that S-OPA1 generation by OPA1 cleavage is a survival mechanism in stressed cells.
-
Mitochondrial Membrane Dynamics—Functional Positioning of OPA1
Antioxidants, 2018Co-Authors: Yisang YoonAbstract:The maintenance of mitochondrial energetics requires the proper regulation of mitochondrial morphology, and vice versa. Mitochondrial dynamins control mitochondrial morphology by mediating fission and fusion. One of them, Optic Atrophy 1 (OPA1), is the mitochondrial inner membrane remodeling protein. OPA1 has a dual role in maintaining mitochondrial morphology and energetics through mediating inner membrane fusion and maintaining the cristae structure. OPA1 is expressed in multiple variant forms through alternative splicing and post-translational proteolytic cleavage, but the functional differences between these variants have not been completely understood. Recent studies generated new information regarding the role of OPA1 cleavage. In this review, we will first provide a brief overview of mitochondrial membrane dynamics by describing fission and fusion that are mediated by mitochondrial dynamins. The second part describes OPA1-mediated fusion and energetic maintenance, the role of OPA1 cleavage, and a new development in OPA1 function, in which we will provide new insight for what OPA1 does and what proteolytic cleavage of OPA1 is for.
-
Transient Contraction of Mitochondria Induces Depolarization through the Inner Membrane Dynamin OPA1 Protein
Journal of Biological Chemistry, 2014Co-Authors: Yisang YoonAbstract:Dynamin-related membrane remodeling proteins regulate mitochondrial morphology by mediating fission and fusion. Although mitochondrial morphology is considered an important factor in maintaining mitochondrial function, a direct mechanistic link between mitochondrial morphology and function has not been defined. We report here a previously unrecognized cellular process of transient contraction of the mitochondrial matrix. Importantly, we found that this transient morphological contraction of mitochondria is accompanied by a reversible loss or decrease of inner membrane potential. Fission deficiency greatly amplified this phenomenon, which functionally exhibited an increase of inner membrane proton leak. We found that electron transport activity is necessary for the morphological contraction of mitochondria. Furthermore, we discovered that silencing the inner membrane-associated dynamin Optic Atrophy 1 (OPA1) in fission deficiency prevented mitochondrial depolarization and decreased proton leak without blocking mitochondrial contraction, indicating that OPA1 is a factor in coupling matrix contraction to mitochondrial depolarization. Our findings show that transient matrix contraction is a novel cellular mechanism regulating mitochondrial activity through the function of the inner membrane dynamin OPA1.
Norihito Shintani - One of the best experts on this subject based on the ideXlab platform.
-
Optic Atrophy 1 is epistatic to the core micos component mic60 in mitochondrial cristae shape control
Cell Reports, 2016Co-Authors: Christina Glytsou, Enrique Calvo, Sara Cogliati, Arpit Mehrotra, Irene Anastasia, Giovanni Rigoni, Andrea Raimondi, Norihito ShintaniAbstract:Summary The mitochondrial contact site and cristae organizing system (MICOS) and Optic Atrophy 1 (OPA1) control cristae shape, thus affecting mitochondrial function and apoptosis. Whether and how they physically and functionally interact is unclear. Here, we provide evidence that OPA1 is epistatic to MICOS in the regulation of cristae shape. Proteomic analysis identifies multiple MICOS components in native OPA1-containing high molecular weight complexes disrupted during cristae remodeling. MIC60, a core MICOS protein, physically interacts with OPA1, and together, they control cristae junction number and stability, OPA1 being epistatic to MIC60. OPA1 defines cristae width and junction diameter independently of MIC60. Our combination of proteomics, biochemistry, genetics, and electron tomography provides a unifying model for mammalian cristae biogenesis by OPA1 and MICOS.
Christina Glytsou - One of the best experts on this subject based on the ideXlab platform.
-
the cristae modulator Optic Atrophy 1 requires mitochondrial atp synthase oligomers to safeguard mitochondrial function
Nature Communications, 2018Co-Authors: Ruben Quintanacabrera, Christina Glytsou, Enrique Calvo, Charlotte Quirin, Mauro Corrado, Andrea Urbani, Anna Pellattiero, Jesus VazquezAbstract:It is unclear how the mitochondrial fusion protein Optic Atrophy 1 (OPA1), which inhibits cristae remodeling, protects from mitochondrial dysfunction. Here we identify the mitochondrial F1Fo-ATP synthase as the effector of OPA1 in mitochondrial protection. In OPA1 overexpressing cells, the loss of proton electrochemical gradient caused by respiratory chain complex III inhibition is blunted and this protection is abolished by the ATP synthase inhibitor oligomycin. Mechanistically, OPA1 and ATP synthase can interact, but recombinant OPA1 fails to promote oligomerization of purified ATP synthase reconstituted in liposomes, suggesting that OPA1 favors ATP synthase oligomerization and reversal activity by modulating cristae shape. When ATP synthase oligomers are genetically destabilized by silencing the key dimerization subunit e, OPA1 is no longer able to preserve mitochondrial function and cell viability upon complex III inhibition. Thus, OPA1 protects mitochondria from respiratory chain inhibition by stabilizing cristae shape and favoring ATP synthase oligomerization.
-
Optic Atrophy 1 is epistatic to the core micos component mic60 in mitochondrial cristae shape control
Cell Reports, 2016Co-Authors: Christina Glytsou, Enrique Calvo, Sara Cogliati, Arpit Mehrotra, Irene Anastasia, Giovanni Rigoni, Andrea Raimondi, Norihito ShintaniAbstract:Summary The mitochondrial contact site and cristae organizing system (MICOS) and Optic Atrophy 1 (OPA1) control cristae shape, thus affecting mitochondrial function and apoptosis. Whether and how they physically and functionally interact is unclear. Here, we provide evidence that OPA1 is epistatic to MICOS in the regulation of cristae shape. Proteomic analysis identifies multiple MICOS components in native OPA1-containing high molecular weight complexes disrupted during cristae remodeling. MIC60, a core MICOS protein, physically interacts with OPA1, and together, they control cristae junction number and stability, OPA1 being epistatic to MIC60. OPA1 defines cristae width and junction diameter independently of MIC60. Our combination of proteomics, biochemistry, genetics, and electron tomography provides a unifying model for mammalian cristae biogenesis by OPA1 and MICOS.