Modular organization of cardiac energy metabolism: energy conversion, transfer and feedback regulation

Guzun, Rita; Käämbre, Tuuli; Bagur, Rafaela; Grichine, Alexeï; Usson, Yves; Varikmaa, Minna; Anmann, Tiia; Tepp, Kersti; Timohhina, Natalja; Shevchuk, Igor; Chekulayev, Vladimir; Boucher, François; Santos, Pierre Dos; Schlattner, Uwe; Wallimann, Theo; Kuznetsov, Andrey V.; Dzeja, Petras P.; Aliev, Mayis; Saks, Valdur

doi:10.1111/apha.12287

Cited by 45 publications

(49 citation statements)

References 171 publications

(250 reference statements)

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“…Actually, a previous study showed that VDAC is involved in cardiac energy metabolism [60]. Although we demonstrated that RNF207 promotes the polyubiquitination of VDAC1, RNF207 does not affect the stability of VDAC1.…”

Section: Discussioncontrasting

confidence: 60%

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

Mizushima

Takahashi

Watanabe

et al. 2016

Journal of Molecular and Cellular Cardiology

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A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction.Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure.Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure.3 Highlights l RNF207 is specifically expressed in the heart. l RNF207 enhances activity of the tricarboxylic acid cycle in cardiomyocytes.l RNF207 directly interacts with VDAC1 through its coiled-coil domain.l Heart failure significantly reduces the expression of RNF207 in mice.4

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Section: Discussioncontrasting

confidence: 60%

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

Mizushima

Takahashi

Watanabe

et al. 2016

Journal of Molecular and Cellular Cardiology

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“…A bulk of energy production is directed to contractile function of the heart. As NADH and FADH2 are generated from both fatty acid oxidation as well as the TCA cycle (and lesser extent from glycolysis), protons are transported through the electrochemical gradient between the mitochondrial matrix and the intermembrane space via the F0F1 ATPase and storage of the resultant chemical energy as ATP bound to membrane-associated cytoskeletal elements (79). …”

Section: Cardiac Energetics Substrate Metabolism and Pathophysiologymentioning

confidence: 99%

“…This compartmentalization of myocardial energetic units helps optimize the efficiency of nutrient and oxygen delivery as well as rapidly regenerating ATP from ADP produced by the contractile elements rather than being dependent on diffusion gradients and a diffuse distribution throughout the cell. ATP and ADP, themselves, appear to be attached to cytoskeletal structures rather than free in the cytosol (79). This is important with regards to being able to control the availability of high-energy phosphates to the cardiac myofilaments.…”

Section: Cardiac Energetics Substrate Metabolism and Pathophysiologymentioning

confidence: 99%

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

Mani

Javaheri

Diwan

2018

Comprehensive Physiology

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Adaptive responses that counter starvation have evolved over millennia to permit organismal survival, including changes at the level of individual organelles, cells, tissues, and organ systems. In the past century, a shift has occurred away from disease caused by insufficient nutrient supply toward overnutrition, leading to obesity and diabetes, atherosclerosis, and cardiometabolic disease. The burden of these diseases has spurred interest in fasting strategies that harness physiological responses to starvation, thus limiting tissue injury during metabolic stress. Insights gained from animal and human studies suggest that intermittent fasting and chronic caloric restriction extend lifespan, decrease risk factors for cardiometabolic and inflammatory disease, limit tissue injury during myocardial stress, and activate a cardioprotective metabolic program. Acute fasting activates autophagy, an intricately orchestrated lysosomal degradative process that sequesters cellular constituents for degradation, and is critical for cardiac homeostasis during fasting. Lysosomes are dynamic cellular organelles that function as incinerators to permit autophagy, as well as degradation of extracellular material internalized by endocytosis, macropinocytosis, and phagocytosis. The last decade has witnessed an explosion of knowledge that has shaped our understanding of lysosomes as central regulators of cellular metabolism and the fasting response. Intriguingly, lysosomes also store nutrients for release during starvation; and function as a nutrient sensing organelle to couple activation of mammalian target of rapamycin to nutrient availability. This article reviews the evidence for how the lysosome, in the guise of a janitor, may be the "undercover boss" directing cellular processes for beneficial effects of intermittent fasting and restoring homeostasis during feast and famine. © 2018 American Physiological Society. Compr Physiol 8:1639-1667, 2018.

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“…Thus, the cytosolic ADP, Pi and Cr signals are transformed into a PCr energy flux maintained by the MtCK reaction. As a result, the reactions catalyzed by different isoforms of compartmentalized CK, organized in intracellular energetic units (ICEUs; Saks et al 2012;Guzun et al 2015), tend to maintain the intracellular metabolic stability Aliev et al 1998;Vendelin et al 2000).…”

Section: Proteolipid Complexes Involving Mitochondrial Creatine Kinasmentioning

confidence: 99%

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

et al. 2016

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There is an increasing body of evidence for local circuits of ATP generation and consumption that are largely independent of global cellular ATP levels. These are mostly based on the formation of multiprotein(-lipid) complexes and diffusion limitations existing in cells at different levels of organization, e.g., due to the viscosity of the cytosolic medium, macromolecular crowding, multiple and bulky intracellular structures, or controlled permeability across membranes. Enzymes generating ATP or GTP are found associated with ATPases and GTPases enabling the direct fueling of these energy-dependent processes, and thereby implying that it is the local and not the global concentration of high-energy metabolites that is functionally relevant. A paradigm for such microcompartmentation is creatine kinase (CK). Cytosolic and mitochondrial isoforms of CK constitute a well established energy buffering and shuttling system whose functions are very much based on local association of CK isoforms with ATP-providing and ATP-consuming processes. Here we review current knowledge on the subcellular localization and direct protein and lipid interactions of CK isoforms, in particular about cytosolic brain-type CK (BCK) much less is known compared to muscle-type CK (MCK). We further present novel data on BCK, based on three different experimental approaches: (1) co-purification experiments, suggesting association of BCK with membrane structures such as synaptic vesicles and mitochondria, involving hydrophobic and electrostatic interactions, respectively; (2) yeast-two-hybrid analysis using cytosolic split-protein assays and the identifying membrane proteins VAMP2, VAMP3 and JWA as putative BCK interaction partners; and (3) phosphorylation experiments, showing that the cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate BCK at serine 6 to trigger BCK localization at the ER, in close vicinity of the highly energy-demanding Ca(2+) ATPase pump. Thus, membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations.

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Modular organization of cardiac energy metabolism: energy conversion, transfer and feedback regulation

Cited by 45 publications

References 171 publications

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

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