Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates adrenergic control of lipolysis

Pidoux, Guillaume; Witczak, Oliwia; Jarnæss, Elisabeth; Myrvold, Linda; Urlaub, Henning; Stokka, Anne Jorunn; Küntziger, Thomas; Taskén, Kjetil

doi:10.1038/emboj.2011.365

Cited by 104 publications

(125 citation statements)

References 69 publications

(110 reference statements)

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“…The fact that Mfn1 does not interact with PLIN1 and that mutation of the GTPase activity of Mfn2 abolishes this binding further testifies for the specificity and relevance of the Mfn2‐PLIN1 interaction. It has been previously proposed that OPA1 could assemble a supramolecular complex containing PKA and perilipin and would be responsible for LD–mitochondria interactions (Pidoux et al , 2011). OPA1, however, generally localizes to the inner mitochondrial membrane, which might force the need for molecular adaptors in order to interact with proteins residing outside of the outer mitochondrial membrane.…”

Section: Discussionmentioning

confidence: 99%

Mfn2 is critical for brown adipose tissue thermogenic function

et al. 2017

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Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine‐tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin‐resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose‐specific Mfn2 knockout (Mfn2‐adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2‐adKO mice were protected from high‐fat diet‐induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole‐body energy homeostasis.

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Section: Discussionmentioning

confidence: 99%

Mfn2 is critical for brown adipose tissue thermogenic function

et al. 2017

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“…Accordingly, protein kinase A anchoring proteins are able to bind to the regulatory subunit of PKA and lead to subcellular compartmentalization of cAMP-PKA signaling (70,71). In adipocytes, it has been reported that optic atrophy 1, a regulator of mitochondrial dynamics, acts as a protein kinase A anchoring protein in lipid droplets and facilitates lipolysis upon stimulation (72). Thus, the regulatory mechanisms of PKA activity and lipolysis by subcellular distribution of RI␣ and RII␤ would be important to pursue in further studies.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Lee

Han

Kong

et al. 2016

Journal of Biological Chemistry

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Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent protein kinase composed of catalytic and regulatory subunits and involved in various physiological phenomena, including lipid metabolism. Here we demonstrated that the stoichiometric balance between catalytic and regulatory subunits is crucial for maintaining basal PKA activity and lipid homeostasis. To uncover the potential roles of each PKA subunit, Caenorhabditis elegans was used to investigate the effects of PKA subunit deficiency. In worms, suppression of PKA via RNAi resulted in severe phenotypes, including shortened life span, decreased egg laying, reduced locomotion, and altered lipid distribution. Similarly, in mammalian adipocytes, suppression of PKA regulatory subunits RI␣ and RII␤ via siRNAs potently stimulated PKA activity, leading to potentiated lipolysis without increasing cAMP levels. Nevertheless, insulin exerted anti-lipolytic effects and restored lipid droplet integrity by antagonizing PKA action. Together, these data implicate the importance of subunit stoichiometry as another regulatory mechanism of PKA activity and lipid metabolism.Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent serine/threonine kinase that mediates various cellular responses, including lipolysis. Since its discovery in the 1950s (1-4), the cAMP-PKA system has become one of the best understood signaling pathways in terms of biochemical properties. PKA is composed of catalytic subunits and cAMP-binding regulatory subunits (5). In the absence of cAMP stimulation, PKA forms an inactive tetramer composed of four subunits with two regulatory and two catalytic subunits. Upon nutritional deprivation or hormonal stimulation, activated adenylyl cyclase produces cAMP from ATP. Then, the regulatory subunit of PKA binds cAMP, causing a conformational change that decreases its affinity for catalytic subunits by ϳ10 4 -fold and leads to the release of active catalytic subunits to phosphorylate target proteins (6, 7).PKA has a wide range of substrates that regulate a number of physiological processes. To date, several hundred PKA target proteins have been identified, and yet new PKA substrates are continually being reported (8, 9). In mammalian adipocytes, numerous studies over the last 40 years have revealed that the cAMP-PKA axis forms a critical node in the regulation of lipolysis. For instance, major components of lipolytic pathways, including hormone-sensitive lipase (Hsl) 2 and perilipin 1 (Plin1), are direct targets of PKA (10, 11). Recently, adipose triglyceride lipase (Atgl) was also reported to be a target of PKA (12, 13). Upon receiving activation signals from molecules such as catecholamine and glucagon, activated PKA phosphorylates Plin1 and HSL to promote the recruitment of HSL to lipid droplets (14, 15). In addition, phosphorylated Plin1 releases comparative gene identification-58 (CGI-58; Abhd5), a coactivator of Atgl, to mediate lipolysis upon PKA activation (16 -20). On the contrary, insulin can activate phosphodiesterase 3B (Pde3b) and reduce cAMP levels (1...

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“…For colocalization between BACE1 and synaptophysin, line profiles from the two fluorescent channels were analyzed using the ImageJ red-green-blue (RGB) Profiler plug-in (41). Briefly, neurons were transfected for BACE1-mRFP together with eGFP or RTN3-eGFP, and the fixed neurons on the coverslip were stained with an antibody against synaptophysin.…”

Section: Methodsmentioning

confidence: 99%

Increased Expression of Reticulon 3 in Neurons Leads to Reduced Axonal Transport of β Site Amyloid Precursor Protein-cleaving Enzyme 1

Deng

Tan

et al. 2013

Journal of Biological Chemistry

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Background: Axonal transport of BACE1 and the regulation of BACE1 synaptic localization remain to be fully characterized. Results: Colocalization of BACE1 with synaptophysin was reduced by overexpression of RTN3. This reduction was due to reduced BACE1 axonal transport. Conclusion: Increased interaction of RTN3 with BACE1 in the soma impacts axonal transport of BACE1. Significance: Changes of BACE1 synaptic localization potentially alter synaptic A␤ generation and amyloid deposition.

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Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates adrenergic control of lipolysis

Cited by 104 publications

References 69 publications

Mfn2 is critical for brown adipose tissue thermogenic function

Mfn2 is critical for brown adipose tissue thermogenic function

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Increased Expression of Reticulon 3 in Neurons Leads to Reduced Axonal Transport of β Site Amyloid Precursor Protein-cleaving Enzyme 1

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