Mitochondrial endocrinology Mitochondria as key to hormones and metabolism
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Leu(UUR) mutation. J. Med. Genet. 33, 621–622 . Yu-Wai-Man, P., Griffiths, P.G., Gorman, G.S., Lourenco, C.M., Wright, A.F., Auer- Grumbach, M., et al., 2010. Multi-system neurological disease is common in patients with OPA1 mutations. Brain 133, 771–786 . A.M. Schaefer et al. / Molecular and Cellular Endocrinology 379 (2013) 2–11 11 Mitochondrial function and insulin secretion Pierre Maechler ⇑ Department of Cell Physiology and Metabolism, Geneva University Medical Centre, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland a r t i c l e i n f o Article history: Available online 20 June 2013 Keywords: b-cell Pancreatic islets Insulin secretion Mitochondria Diabetes a b s t r a c t In the endocrine fraction of the pancreas, the b-cell rapidly reacts to fluctuations in blood glucose concen- trations by adjusting the rate of insulin secretion. Glucose-sensing coupled to insulin exocytosis depends on transduction of metabolic signals into intracellular messengers recognized by the secretory machin- ery. Mitochondria play a central role in this process by connecting glucose metabolism to insulin release. Mitochondrial activity is primarily regulated by metabolic fluxes, but also by dynamic morphology changes and free Ca 2+ concentrations. Recent advances of mitochondrial Ca 2+ homeostasis are discussed; in particular the roles of the newly-identified mitochondrial Ca 2+ uniporter MCU and its regulatory part- ner MICU1, as well as the mitochondrial Na + –Ca 2+ exchanger. This review describes how mitochondria function both as sensors and generators of metabolic signals; such as NADPH, long chain acyl-CoA, glu- tamate. The coupling factors are additive to the Ca 2+ signal and participate to the amplifying pathway of glucose-stimulated insulin secretion. Ó 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction 1.1. The pancreatic b-cell Glucose homeostasis depends on optimal regulation of insulin secretion from the b-cells and the action of insulin on its target tis- sues; in particular muscles, liver, and adipose tissue. The b-cells are located in the endocrine fraction of the pancreas, i.e., the islets of Langerhans. In humans, b-cells constitute about 70% of the islets of Langerhans, which are spread throughout the pancreas and compose 1–2% of this organ ( Rahier et al., 1983 ). It means that among the 10 13 –10
14 of cells composing our body, the 10 9 b-cells
contribute to less than 0.01% of this count. In other words, one sin- gle drop of blood contains as much red blood cells as our whole body contains b-cells. Nevertheless, this minute amount of endo- crine tissue is essential for life since there is no alternative hor- mone to insulin, as dramatically illustrated by patients suffering from type 1 diabetes. The cytoplasm of each b-cell contains about 13,000 secretory granules filled with crystallized insulin ( Dean,
1973 ). During glucose stimulation only a small proportion of the granule pool undergoes exocytosis. 1.2. Diabetes and the b-cell The initial stages of type 1 diabetes, before b-cell destruction, are characterized by defects in the function of b-cells ( O’Sullivan- Murphy and Urano, 2012 ). The large majority of diabetic patients are classified as type 2 diabetes, or non-insulin dependent diabetes mellitus. The patients display dysregulation of insulin secretion, of- ten combined with insulin resistance of target tissues. The aetiol- ogy of type 2 diabetes is still poorly understood and has been elucidated in only a limited number of subtypes. Among these, maturity onset diabetes of the young (MODY) and mitochondrial diabetes have been linked to specific gene mutations and primary b-cell dysfunction ( Froguel et al., 1993; Byrne et al., 1996; Clocquet et al., 2000; Maassen et al., 2004 ). The impact of such mutations on the b-cell highlights the importance of the mitochondria in the control of insulin secretion. Other endocrine tissues play an impor- tant role in metabolic dysregulation and the reader is referred to the other articles of this special issue of Molecular and Cellular Endocrinology for corresponding information. 1.3. Metabolic activation of the b-cell Both the secretion and the action of insulin contribute to glu- cose homeostasis. Regulated insulin release requires tight coupling in the b-cell between glucose metabolism and insulin secretory re- sponse. The exocytotic process is closely controlled by signals gen- erated by nutrient metabolism ( Fig. 1 ), as well as by neurotransmitters and circulating hormones ( Huypens et al., 2000; Schuit et al., 2001; Rubi and Maechler, 2010 ). The b-cell rap- idly reacts to fluctuations in the blood glucose concentration by adjusting the rate of insulin secretion. This review describes the molecular basis of metabolism–secretion coupling. In particular, it will be discussed how mitochondria function both as sensors and generators of metabolic signals. 0303-7207/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mce.2013.06.019 ⇑ Tel.: +41 22 379 55 54. E-mail address: Pierre.Maechler@unige.ch Molecular and Cellular Endocrinology 379 (2013) 12–18 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e
2. Overview of metabolism–secretion coupling in b-cells 2.1. Pathways upstream of mitochondria In b-cells, metabolism–secretion coupling refers to both the consensus model and the contribution of additional coupling fac- tors, i.e., the trigger and amplifying pathways of glucose-stimu- lated insulin secretion ( Fig. 1 ). This process is initiated by the passive entry of glucose within the b-cell across the plasma mem- brane through GLUT2 and its subsequent phosphorylation by glu- cokinase, thereby promoting glycolysis ( Iynedjian, 2009 ). In the cytosolic compartment, glycolysis extracts reducing equivalents transmitted to NADH. Maintenance of glycolytic flux requires reox- idation of NADH to NAD + to avoid arrest of glycolysis. In most tissues, cytosolic conversion of pyruvate to lactate by the lactate dehydrogenase ensures NADH oxidation to NAD + , while
in b-cells this task is devoted mainly to mitochondrial NADH shut- tles, transferring glycolysis-derived electrons to mitochondria. 2.2. The mitochondrial NADH shuttle system The mitochondrial NADH shuttle system is composed of the glycerolphosphate and the malate/aspartate shuttles ( MacDonald, 1982 ), with its respective key members the mitochondrial glycerol phosphate dehydrogenase (mGPDH) and the aspartate–glutamate carrier (AGC). The aspartate–glutamate carrier 1 (AGC1, also named Aralar1) is a Ca 2+ -sensitive member of the malate/aspartate shuttle ( del Arco and Satrustegui, 1998 ). Overexpression of AGC1 increases glucose-induced mitochondrial activation and secretory response, both in insulinoma INS-1E cells and rat islets ( Rubi
et al., 2004 ). This is accompanied by enhanced glucose oxidation and reduced lactate production. In insulinoma INS-1E b-cells, the mirror experiment consisting in silencing AGC1 reduces glucose oxidation and the secretory response, although primary rat b-cells are not sensitive to such a manoeuvre ( Casimir et al., 2009 ). There- fore, aspartate–glutamate carrier capacity appears to set a limit for NADH shuttle function and mitochondrial metabolism, exhibiting cell type-specific dependence. The importance of the NADH shuttle system illustrates the tight coupling between glycolysis and mito- chondrial activation in b-cells, optimizing transfer of pyruvate into mitochondria through the recently identified mitochondrial pyru- vate carrier ( Herzig et al., 2012 ). Subsequently, catabolism of glu- cose-derived pyruvate induces mitochondrial activation resulting in ATP generation. Although mitochondria, and the Krebs cycle in particular, also oxidize fatty acids and amino acids, carbohydrates are the most important fuel under physiological conditions for the b-cell.
2.3. Pathways downstream of mitochondria Export of ATP to the cytosolic compartment promotes the clo- sure of ATP-sensitive K + -channels (K ATP -channel) on the plasma membrane and, as a consequence, depolarization of the cell ( Ash-
croft, 2006 ). This leads to Ca 2+ influx through voltage-gated Ca 2+ channels and a rise in cytosolic Ca 2+ concentrations ( Fig. 1 ), which
is the main and necessary signal for exocytosis of insulin ( Eliasson
et al., 2008 ). Additional signals are required to sustain the secretion elicited by glucose-induced Ca 2+ rise. They participate in the ampli- fying pathway ( Maechler et al., 2006 ), formerly referred to as the K ATP -channel independent stimulation of insulin secretion. Effi- cient coupling of glucose recognition to insulin secretion is ensured by the mitochondrion, an organelle that integrates and generates metabolic signals ( Maechler et al., 2006 ). This role is additive to the generation of ATP necessary for the elevation of cytosolic Ca 2+ . The list of additive factors proposed to amplify the Ca 2+ sig- nals comprises cAMP, NADPH, long chain acyl-CoA derivatives, glu- tamate, and superoxides. As opposed to the recognized primary role of Ca 2+ as a necessary signal, the roles of most of these additive factors are still under debate. 3. Metabolic activation of mitochondria 3.1. Activation of the Krebs cycle Pyruvate entry within the mitochondria induces metabolic acti- vation of this organelle. There, pyruvate either loses one carbon to Fig. 1. Model for coupling of glucose metabolism to insulin secretion in the b-cell. Glucose equilibrates across the plasma membrane and is phosphorylated by glucokinase (GK). Further, glycolysis produces pyruvate, which preferentially enters the mitochondria and is metabolized by the TCA cycle. The TCA cycle generates reducing equivalents transferred by NADH and FADH 2 to the electron transport chain (ETC), leading to hyperpolarization of the mitochondrial membrane (D w m ) and generation of ATP. ATP is then transferred to the cytosol, raising the ATP/ADP ratio. Subsequently, closure of K ATP
-channels depolarizes the cell membrane (D w c ). This opens voltage-dependent Ca 2+ channels, increasing cytosolic Ca 2+ concentration ([Ca 2+ ]
), which triggers insulin exocytosis. The amplifying pathway of metabolism–secretion coupling is contributed by additive coupling factors. P. Maechler / Molecular and Cellular Endocrinology 379 (2013) 12–18 13
generate acetyl-CoA or gains one carbon to form oxaloacetate; reactions catalyzed by pyruvate dehydrogenase (PDH) and pyru- vate carboxylase (PC), respectively ( Fig. 2
). PDH is an important site of regulation as, among other effectors, the enzyme is activated by an elevation of mitochondrial [Ca 2+ ] ( Duchen, 1999; Rutter et al., 1996 ). PDH is also regulated by reversible phosphorylation of its E1 a subunit, activity of the PDH kinases inhibiting the en- zyme ( Sugden and Holness, 2003 ). Increasing the expression of either the PDH phosphatase or the PDH kinase 3 does not change glucose-stimulated insulin secretion ( Nicholls, 2002 ). Regarding down-regulation of PDH kinases, silencing of PDH kinase 1 in INS-1 832/13 cells has been reported to increase the secretory re- sponse to glucose ( Krus et al., 2010 ), whereas knockdown of both PDH kinase 1 and kinase 3 in INS-1E cells does not affect metabo- lism–secretion coupling ( Akhmedov et al., 2012 ). Therefore, the importance of the phosphorylation state of PDH for the regulation of b-cell function remains unclear. Condensation of the 2-carbon acetyl group carried by coen- zyme-A with the 4-carbon oxaloacetate yields citrate, thereby acti- vating the tricarboxylic acid (TCA) cycle (or Krebs cycle). The pyruvate carboxylase enzyme ensures the provision of carbon skel- eton (i.e., anaplerosis) to the TCA cycle, a key pathway in b-cells ( Fransson et al., 2006 ). The remarkably high anaplerotic activity in b-cells indicates important loss of TCA cycle intermediates (i.e., cataplerosis), which is compensated for by de novo oxaloace- tate synthesis by pyruvate carboxylation. In the control of glu- cose-stimulated insulin secretion, TCA cycle intermediates are recruited to serve as substrates leading to the formation of mito- chondrion-derived coupling factors ( Maechler et al., 2006 ). Through its oxidative activity, the TCA cycle extracts reducing equivalents from metabolic intermediates, which are then trans- ported mainly by NADH and, quantitatively less important, by FADH 2
TCA cycle upon glucose stimulation, this reduced redox state re- quires continues reoxidation of mitochondrial NADH to NAD + . This
is achieved primarily by complex I NADH dehydrogenase on the electron transport chain. However, as complex I activity is limited by the inherent thermodynamic constraints of proton gradient for- mation, excess of NADH contributed by the high TCA cycle activity must be reoxidized by alternative dehydrogenases, i.e., through cataplerotic reactions. 3.2. Activation of the electron transport chain TCA cycle activation induces transfer of reducing equivalents to the electron transport chain resulting in hyperpolarization of the mitochondrial membrane, respiration, and generation of ATP ( Fig. 2
). Electron transport chain activity promotes proton export from the mitochondrial matrix across the inner membrane, estab- lishing a strong mitochondrial membrane potential, which is neg- ative on the inside. The respiratory chain comprises five complexes, the subunits of which are encoded by both the nuclear and mitochondrial genomes ( Wallace, 1999 ). Complex I is the acceptor of electrons from NADH in the inner mitochondrial mem- brane and complex II (succinate dehydrogenase) transfers elec- trons to coenzyme-Q from FADH 2 , the latter being generated both by the oxidative activity of the TCA cycle and the glycerol- phosphate shuttle. Complex V (ATP synthase) promotes ATP for- mation from ADP and inorganic phosphate. The synthesized ATP is translocated to the cytosol in exchange for ADP by the adenine nucleotide translocator (ANT). Thus, the actions of the separate complexes of the electron transport chain and the adenine nucleo- tide translocator couple respiration to ATP supply. 3.3. Regulation of mitochondrial activity by Ca 2+ Mitochondrial activity can be modulated according to the nat- ure of the nutrients, although glucose is the chief secretagogue as compared to amino acid catabolism ( Newsholme et al., 2005 ) and
fatty acid b-oxidation ( Rubi et al., 2002 ). Additional factors regulat- ing mitochondrial activation include mitochondrial Ca 2+ concen-
trations ([Ca 2+ ] m ) (
Duchen, 1999; McCormack et al., 1990 ), Fig. 2. In the mitochondria, pyruvate (Pyr) is a substrate both for pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC), forming respectively acetyl-CoA and oxaloacetate (OA). Condensation acetyl-CoA with OA generates citrate that is either processed by the TCA cycle or exported out of the mitochondrion as a precursor for long chain acyl-CoA (LC-CoA) synthesis. The glycerophosphate and malate/aspartate shuttles, as well as the TCA cycle, generate reducing equivalents in the form of NADH and FADH 2
w m ) and the synthesis of ATP, then transported to the cytosol by the adenine nucleotide translocator (ANT). Upon glucose stimulation, glutamate (Glut) is produced from a -ketoglutarate ( a KG) by glutamate dehydrogenase (GDH) and exported out of mitochondria through the glutamate carrier (GC1). Ca 2+ enters into mitochondria via MCU (regulated by MICU1) and gets out via NCLX . 14 P. Maechler / Molecular and Cellular Endocrinology 379 (2013) 12–18 mitochondrial protein tyrosine phosphatase ( Pagliarini et al., 2005 ), mitochondrial GTP ( Kibbey et al., 2007 ), and matrix alkalin- ization ( Wiederkehr et al., 2009 ). Among these factors, mitochon- drial Ca
2+ regulation has recently been highlighted, thanks to a series of discoveries related to Ca 2+ transport through the mito- chondrial membrane. Elevation of [Ca 2+ ] m enhances mitochondrial oxidative activity ( Maechler et al., 1998 ) and promotes generation of coupling factors for insulin exocytosis ( Maechler et al., 1997 ). Conversely, buffering mitochondrial free Ca 2+ limits [Ca 2+ ]
peaks induced by glucose stimulation in INS-1E b-cells. Such limitation in [Ca 2+
m amplitude reduces mitochondrial respiration and ATP generation with corresponding effects on insulin secretion ( Wie-
derkehr et al., 2011 ). In the recent years, significant advances in mitochondrial Ca 2+ channels have been made. In 2011, the mitochondrial Ca 2+ uni-
porter (MCU) has been identified as the channel responsible for mitochondrial Ca 2+ uptake (
Baughman et al., 2011; De Stefani et al., 2011 ). MCU is part of a complex located in the inner mito- chondrial membrane and its activity is modulated by another re- cently identified protein, the mitochondrial Ca 2+ uptake 1 (MICU1). MICU1 holds Ca 2+ sensing subunits, in other words two canonical EF hands, which are essential for its activity ( Perocchi
et al., 2010 ). If Ca
2+ gets in mitochondria, it should also get out at some point, although the vast majority of mitochondrial Ca 2+ is buffered as chelated ion. Mitochondrial Ca 2+ efflux is thought to be mediated by the Na 2+ /Ca 2+ exchanger (NCLX) identified in 2010 ( Palty et al., 2010 ). Therefore, MCU and MICU1 would be implicated in mitochondrial Ca 2+ uptake, whereas NCLX would be responsible for Ca 2+ efflux ( Fig. 2 ). In pancreatic b-cells, silencing of NCLX extends elevations of [Ca 2+ ] m evoked by cell depolarization and also accelerates the rise in ATP/ADP ratio in response to glucose stimulation ( Tarasov et al., 2012 ). Consistently, the rise in [Ca 2+ ] m evoked by glucose is en- hanced in b-cells when NCLX is silenced or expressed in a domi- nant negative form ( Nita et al., 2012 ). These recent data are in agreement with a previous study showing increased mitochondrial metabolism and enhanced glucose-stimulated insulin secretion when the Na 2+ /Ca
2+ exchanger was pharmacologically inhibited by CGP37157 ( Lee et al., 2003 ). Regarding the role of NCLX in ATP production, the inhibitor CGP37157 increases glucose-induced ATP generation, whereas knockdown of NCLX using siRNA does not ( Nita et al., 2012 ), suggesting additional effects of CGP37157. Ca 2+ import into mitochondria is regulated by the recently iden- tified MCU ( Baughman et al., 2011; De Stefani et al., 2011 ) and
MICU1 ( Perocchi et al., 2010 ). Silencing of MCU in b-cells impairs the rise in [Ca 2+ ]
evoked by cell depolarization and reduces the plateau phase of ATP/ADP ratio upon glucose stimulation ( Tarasov et al., 2012 ). Accordingly, knockdown of MCU in mouse b-cells inhibits glucose-induced exocytosis ( Tarasov et al., 2013 ). Such
manipulation of [Ca 2+ ] m does not affect mitochondrial membrane potential, either at basal or stimulatory glucose concentrations ( Tarasov et al., 2012 ). Regarding MICU1, its silencing in insulinoma cells reduces mitochondrial Ca 2+ uptake, ATP levels, and insulin secretion upon glucose stimulation ( Alam et al., 2012 ). In the same study, knockdown of MCU provoked similar inhibitory effects ( Alam et al., 2012 ). Collectively, these recent findings indicate that both the channel and its regulatory partner, i.e., MCU and MICU1 respectively, are necessary for proper regulation of [Ca 2+ ] m in b-
cells and participate to glucose-stimulated insulin secretion. 3.4. Regulation of mitochondrial dynamics Mitochondrial activation also involves changes in organelle morphology and contacts, in particular with the Ca 2+ -rich endo- plasmic reticulum ( de Brito and Scorrano, 2010 ). Mitochondria form dynamic networks, continuously modified by fission and fusion events under the control of specific mitochondrial mem- brane anchor proteins ( Westermann, 2008 ). Over the last years, mitochondrial fission/fusion state was investigated in insulin secreting cells. Altering fission by down regulation of fission-pro- moting Fis1 protein impairs respiratory function and glucose-stim- ulated insulin secretion ( Twig et al., 2008 ). Intriguingly, a similar phenotype, i.e., reduced energy metabolism and secretory defects, is caused by the mirror experiment consisting in mitochondrial fragmentation by overexpression of Fis1 ( Park et al., 2008 ). Adding puzzlement to our comprehension of mitochondrial dynamics in b- cell function, fragmented pattern obtained by dominant-negative expression of fusion-promoting Mfn1 protein does not affect metabolism–secretion coupling ( Park et al., 2008 ). Recently, it was reported that glucose stimulation of INS-1E cells induces reversible shortening of mitochondrial tubules ( Jhun et al., 2013 ). Expression of a dominant-negative mutant of fission-promoting Drp1 prevents glucose-induced mitochondria shortening and insu- lin secretion ( Jhun et al., 2013 ). Therefore, mitochondrial fragmen- tation per se seems not to alter insulin secreting cells, at least not in vitro
. Regarding Ca 2+ homeostasis, mitochondrial fragmentation in mouse b-cells lacking prohibitin-2 is associated with blunted glucose-induced Ca 2+ rise but preserved KCl response; indicating that ATP generation rather than Ca 2+ channels is defective in these cells (S. Supale and P. Maechler, unpublished observation). In vivo, transgenic mice with b-cell-specific ablation of fusion-promoting Opa1 are hyperglycaemic. Islets from these mice exhibit disman- tled mitochondrial architecture, reduced ATP generation and insu- lin release ( Zhang et al., 2011 ). Additionally, b-cell proliferation is reduced in b-cell-specific Opa1-deficient mice ( Zhang et al., 2011 ). 4. Mitochondria as the source of additional coupling factors for insulin exocytosis 4.1. Mitochondria as a source of coupling factors Glucose metabolism induces the triggering and the amplifying pathways, in other words the necessary Ca 2+ rise and generation of additional coupling factors, respectively ( Henquin, 2000 ). The amplifying pathway can be experimentally uncovered when glu- cose stimulation occurs whilst cytosolic Ca 2+ is clamped at permis- sive levels ( Gembal et al., 1992 ). This suggests the existence of metabolic coupling factors, generated by glucose, participating to the amplifying pathway. Mitochondria have been identified as a source of additional coupling factors for insulin exocytosis. For in- stance, the demonstration has been done using permeabilized insulin-secreting cells clamped with permissive Ca 2+ concentra- tions and stimulated with mitochondrial substrates ( Maechler
et al., 1997 ). 4.2. Mitochondria as a source of nucleotides serving as coupling factors ATP is undoubtedly the primary metabolic factor produced by mitochondria during glucose-stimulated insulin secretion. ATP closes the K ATP
-channel leading to the obligatory Ca 2+ elevation promoting insulin exocytosis ( Miki et al., 1999 ). Moreover, ATP is implicated in secretory granule movement ( Yu et al., 2000; Varadi et al., 2002 ), priming of the granules prior to exocytosis ( Eliasson
et al., 1997 ), and in the process of insulin exocytosis per se ( Vallar et al., 1987; Rorsman et al., 2000 ). The purine nucleoside GTP is also implicated to some extent in the process of metabolism–secretion coupling. In the cytosol, GTP is mainly generated through the action of nucleoside diphosphate kinase from ATP-dependent phosphorylation of GDP. Glucose stim- ulation raises GTP levels ( Detimary et al., 1996 ), promoting insulin exocytosis via the activity of GTPases ( Vallar et al., 1987 ). In P. Maechler / Molecular and Cellular Endocrinology 379 (2013) 12–18 15 mitochondria, GTP acts as a positive regulator of the TCA cycle ( Kibbey et al., 2007 ). NADH and its phosphorylated form NADPH are responsible for transfer of reducing equivalents in biochemical pathways. NADPH is mostly found in the cytosolic compartment, whilst NADH is par- ticularly abundant in mitochondria. Glucose stimulation modifies the redox state of these pyridine nucleotides, raising the NAD(P)H/NAD(P) + ratio ( Capito et al., 1984 ), first in the cytosol and then in mitochondria ( Patterson et al., 2000 ). Consistent with the model of metabolism–secretion coupling, increase in NAD(P)H precedes the elevation in cytosolic Ca 2+ concentrations ( Pralong et al., 1990 ). Beside the rapid changes in NAD(P)H/NAD(P) + ratio, the total pool of NADPH is elevated upon glucose stimulation through the phosphorylating activity of NAD-kinase ( Gray et al., 2012
). Cytosolic NADPH is generated by glucose metabolism via the pentose phosphate shunt ( Verspohl et al., 1979 ), although in b- cells mitochondrial shuttles appear to play an important role in this process ( Farfari et al., 2000 ). The export of citrate out of the mitochondria might serve as a signal of fuel abundance, participat- ing in metabolism–secretion coupling ( Farfari et al., 2000 ). Once in the cytosolic compartment, citrate metabolism contributes to the formation of NADPH and malonyl-CoA, both candidate molecules on the list of metabolic coupling factors. NADPH has been proposed as a coupling factor in glucose-stim- ulated insulin secretion, originally by using toadfish islets ( Watkins et al., 1968 ) indicating a direct effect of NADPH on the release of insulin ( Watkins, 1972 ) secondary to the uptake of NADPH by granules ( Watkins and Moore, 1977 ). Subsequently, the role of NADPH as a coupling factor has been substantiated by experiments showing direct stimulation of insulin exocytosis upon intracellular addition of NADPH ( Ivarsson et al., 2005 ). It has also been reported that the NADPH/NADP + ratio mediates a fast-inactivating K + cur-
rent through regulation of Kv2.1 channels ( MacDonald et al., 2003 ). Finally, the second messenger cAMP robustly potentiates glu- cose-stimulated insulin secretion ( Ahren, 2000 ). Glucose stimula- tion can promote elevation of cAMP ( Charles et al., 1975 ) that is generated by adenylyl cyclase at the plasma membrane using ATP. The cAMP levels are negatively modulated by superoxide, an effect mediated by NADPH oxidases ( Li et al., 2012 ). In particular, the glucose response of islets deficient in NOX2 is characterized by lower superoxide, higher cAMP levels, and increased insulin secretion ( Li et al., 2012 ). Among other hormones, glucagon and GLP-1 (glucagon-like peptide 1) increase cAMP concentrations in b-cells ( Schuit et al., 2001 ), resulting in the amplification of the secretory response to glucose in human islets ( Huypens et al., 2000 ). In addition to its effects on insulin release, GLP-1 might pre- serve b-cell mass, rendering this hormone and biologically active related molecules of interest for the treatment of diabetes ( Drucker and Nauck, 2006 ). 4.3. Mitochondria as a source of precursors for fatty acids serving as coupling factors The relative contribution of glucose versus lipid products for oxidative catabolism shapes the metabolic profile of mitochondria. The rate-limiting step for transport and oxidation of fatty acids into mitochondria is catalyzed by carnitine palmitoyltransferase (the li- ver isoform LCPTI in the b-cell). Upon glucose stimulation, citrate derived from mitochondria reacts with coenzyme-A (CoA) to gen- erate cytosolic acetyl-CoA necessary for the synthesis malonyl- CoA and then long-chain acyl-CoA. The malonyl-CoA thus formed reduces fatty acid oxidation by inhibiting LCPTI. The hypothesis that malonyl-CoA/long-chain acyl-CoA act as coupling factors in the secretory response was originally based on the inhibition of fatty acid oxidation by malonyl-CoA, which increases the availabil- ity of lipid signals implicated in exocytosis ( Brun et al., 1996 ). In
the cytosol, this process promotes the accumulation of long chain acyl-CoAs such as palmitoyl-CoA ( Liang and Matschinsky, 1991; Prentki et al., 1992 ), enhancing Ca 2+ -evoked insulin exocytosis ( Deeney et al., 2000 ). Accordingly, LCPTI overexpression in INS- 1E b-cells increases oxidation of fatty acids, whilst it reduces glu- cose-stimulated insulin secretion ( Rubi et al., 2002 ). To date, the exact role of long chain acyl-CoA derivatives is still debated, sev- eral studies indicating that malonyl-CoA acts as a factor regulating the partitioning of fatty acids into effectors in insulin exocytosis ( Prentki et al., 2002 ). Fatty acids derived from triglyceride stores may also play a permissive role in the secretory response ( Frigerio et al., 2010; Peyot et al., 2009 ). 4.4. Mitochondria as a source of glutamate serving as coupling factor The observation of direct stimulation of insulin exocytosis by mitochondrial activation in permeabilized b-cells ( Maechler et al., 1997 ) led to the identification of glutamate as a putative intracellular messenger ( Maechler and Wollheim, 1999; Hoy et al., 2002; Maechler et al., 2002 ). Collectively, work from our lab- oratory and others indicate that permissive levels of glutamate are necessary for the full development of the secretory response to glucose stimulation. The cytosolic target of glutamate might be the insulin granule itself, as several studies by different groups have shown requirement of glutamate uptake by secretory vesicles for insulin exocytosis ( Maechler and Wollheim, 1999; Hoy et al., 2002; Eto et al., 2003; Gammelsaeter et al., 2011; Storto et al., 2006
). If intracellular glutamate renders insulin granules exocytosis- competent, concentrations of this amino acid should raise in re- sponse to glucose stimulation. Indeed, during glucose stimulation total cellular glutamate levels have been shown to increase in hu- man, mouse and rat islets as well as in clonal b-cells ( Maechler and Wollheim, 1999; Rubi et al., 2001; Brennan et al., 2002; Bertrand et al., 2002; Broca et al., 2003; Carobbio et al., 2004; Lehtihet et al., 2005 ), When b-cells are forced to express an enzyme that decarboxylates intracellular glutamate, the glucose-induced gluta- mate rise is impaired as well as the secretory response ( Rubi et al., 2001 ). The mitochondrial enzyme glutamate dehydrogenase (GDH), encoded by Glud1, plays a key role in glucose-induced glu- tamate generation ( Fig. 2 ). Abrogation of GDH specifically in the b- cells of bGlud1 À/À
mice reduces the secretory response ( Carobbio
et al., 2009 ). Moreover, measurements of carbon fluxes in mouse islets revealed that, upon glucose stimulation, GDH contributes to the net synthesis of glutamate from the TCA cycle intermediate a -ketoglutarate ( Vetterli et al., 2012 ). In b-cells lacking GDH, glu- cose-stimulated insulin secretion is reduced by half, correlating with impaired glutamate formation while the Ca 2+ rise is preserved ( Vetterli et al., 2012 ). Importantly, the amplifying pathway charac- terizing the full development of the glucose response fails to devel- op in the absence of GDH, as demonstrated in bGlud1 À/À
islets ( Vetterli et al., 2012 ). Regarding export of the newly synthesized glutamate out of mitochondria, the glutamate carrier GC1 seems to play an impor- tant role. Silencing of GC1 reduces glucose-stimulated insulin secretion, an effect rescued by the provision of exogenous gluta- mate to the b-cell ( Casimir et al., 2009 ). Finally, prevention of glu- tamate release from b-cells results in concomitant elevations of intracellular glutamate levels and glucose-evoked insulin secretion ( Feldmann et al., 2011 ). Collectively, data indicate that permissive levels of glutamate are required in the amplifying pathway of the b-cell. Permissive concentrations of glutamate are also important for proper function of the malate–aspartate shuttle, an key player in insulin secreting cells ( Rubi et al., 2004; Casimir et al, 2009 ), as discussed above. 16 P. Maechler / Molecular and Cellular Endocrinology 379 (2013) 12–18 5. Conclusion In pancreatic b-cells, mitochondrial activity translates glucose metabolism into signals controlling the rate of insulin exocytosis. Consequently, mitochondrial function can adjust insulin secretion to the actual glycemia. This role is specific for b-cells, since in most cell types mitochondrial metabolism is triggered by specific needs of the cells, in terms of energy and building blocks. In b-cells, mito- chondrial metabolism is primarily dictated by the glycolytic flux. The concept of metabolism–secretion coupling that characterizes the b-cell is tightly controlled by on and off signals, most of them requiring mitochondrial function. Future studies should better de- fine the molecular targets and mechanism of action of coupling factors controlling insulin secretion. Acknowledgments The author’s laboratory benefits from continuous support by the Swiss National Science Foundation and the State of Geneva. The most precious contribution of present and past members of the laboratory is acknowledged. References Ahren, B., 2000. Autonomic regulation of islet hormone secretion–implications for health and disease. Diabetologia 43, 393–410 . Akhmedov, D., De Marchi, U., Wollheim, C.B., Wiederkehr, A., 2012. Pyruvate dehydrogenase E1alpha phosphorylation is induced by glucose but does not control metabolism–secretion coupling in INS-1E clonal beta-cells. Biochim. Biophys. Acta 1823, 1815–1824 . Alam, M.R., Groschner, L.N., Parichatikanond, W., Kuo, L., Bondarenko, A.I., Rost, R., Waldeck-Weiermair, M., Malli, R., Graier, W.F., 2012. Mitochondrial Ca 2+ uptake 1 (MICU1) and mitochondrial Ca 2+ uniporter (MCU) contribute to metabolism– secretion coupling in clonal pancreatic beta-cells. J. Biol. Chem. 287, 34445– 34454
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Mitochondrial and skeletal muscle health with advancing age Adam R. Konopka, K. Sreekumaran Nair ⇑ Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, United States a r t i c l e i n f o Article history: Available online 16 May 2013 Keywords: Aging Sarcopenia Mitochondria Protein metabolism a b s t r a c t With increasing age there is a temporal relationship between the decline of mitochondrial and skeletal muscle volume, quality and function (i.e., health). Reduced mitochondrial mRNA expression, protein abundance, and protein synthesis rates appear to promote the decline of mitochondrial protein quality and function. Decreased mitochondrial function is suspected to impede energy demanding processes such as skeletal muscle protein turnover, which is critical for maintaining protein quality and thus skel- etal muscle health with advancing age. The focus of this review was to discuss promising human phys- iological systems underpinning the decline of mitochondrial and skeletal muscle health with advancing age while highlighting therapeutic strategies such as aerobic exercise and caloric restriction for combat- ing age-related functional impairments. Ó 2013 Published by Elsevier Ireland Ltd. 1. Introduction Reports of skeletal muscle atrophy that accompany advancing age (i.e., sarcopenia) and the associated reductions in skeletal mus- cle function and quality have been observed for several decades ( Critchley, 1931; Rosenberg, 1989, 1997 ). Recently, panels of lead- ing scientists and physicians associated with large-scale epidemio- logical studies have created specific, objective criteria based on lean tissue mass and functional capacity to improve the diagnosis and treatment of sarcopenia ( Delmonico et al., 2007; Fielding et al., 2011; Goodpaster et al., 2006; Morley et al., 2011; Newman et al., 2003
). Human aging starts after the third decade and the progres- sion of skeletal muscle atrophy with age is a slow process (1% per year), but accelerates as humans approach 80 years of age ( Baum-
gartner et al., 1998 ). With expansion in human lifespan, the ele- vated rate of muscle loss becomes more problematic since skeletal muscle is critical for functionality and substrate metabo- lism. When the substrate reservoir deteriorates with age, the asso- ciated cardiometabolic disease states (i.e. insulin resistance, diabetes, cardiovascular disease, obesity) become more prevalent ( Atlantis et al., 2009 ). Many studies have observed reduced skeletal muscle mass and infiltration of adipose tissue depots within or be- tween skeletal muscle groups that are associated with reduced muscle function, insulin resistance and obesity ( Delmonico et al., 2009; Goodpaster et al., 2005, 2000 ). A key link between a reduc- tion in skeletal muscle health and prevalence of metabolic disor- ders with advancing age may be related to impaired mitochondrial function. A reduction in mitochondrial abundance and function with age has been observed across various species (c elegans, drosphilla, mice, humans) and tissues (skin, nerve, brain, skeletal muscle). Moreover, perturbations in skeletal muscle mitochondrial energetics have been correlated with reduced aero- bic capacity ( Short et al., 2005a ), walking capacity ( Coen et al., 2012 ) and skeletal muscle function ( Safdar et al., 2010 ) in older adults. The mechanisms of age-related changes in skeletal muscle are multifactorial but the purpose of this review is to highlight the apparent temporal and functional connection between the de- cline of mitochondrial and skeletal muscle health ( Fig. 1 ).
Electron microscopic assessment of skeletal muscle biopsy sam- ples revealed lower mitochondrial volume density in older adults ( Conley et al., 2000 ). A decline in mitochondrial content, as repre- sented by mitochondrial DNA copy number, has also been demon- strated in rodents ( Barazzoni et al., 2000 ) and humans ( Short et al., 2005a ). These findings, coupled with investigations that observed reduced levels of mitochondrial protein synthesis ( Rooyackers et al., 1996 ) and expression of proteins encoded by both mitochon- drial and nuclear DNA ( Lanza et al., 2008; Short et al., 2005a ), are expected to alter mitochondrial function. Semi-quantitative analy- ses, such as immunoblotting or maximal enzyme activity, support the notion that aging skeletal muscle contains less abundance of enzymes in oxidative metabolism (i.e. Krebs Cycle, beta-oxidation) and/or proteins involved in the electron transport chain (ETC) ( Coo- per et al., 1992; Ghosh et al., 2011; Lanza et al., 2008; Rooyackers et al., 1996; Tonkonogi et al., 2003; Trounce et al., 1989 ). Collec- tively, reductions in mitochondrial proteins and volume may limit 0303-7207/$ - see front matter Ó 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.mce.2013.05.008 ⇑ Corresponding author. Address: Mayo Clinic, 200 First St. SW, Joseph 5-194, Rochester, MN, United States. Tel.: +1 507 255 2415; fax: +1 507 255 4828. E-mail address: nair.sree@mayo.edu (K. Sreekumaran Nair). Molecular and Cellular Endocrinology 379 (2013) 19–29 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e
ATP production for energy demanding processes such as myocellu- lar remodeling to maintain protein quality. Advancements of in vitro and ex vivo measures of mitochondrial energetics have detected diminished capacity for basal ( Petersen et al., 2003 ) and maximal ( Conley et al., 2000; Kent-Braun and Ng, 2000; Short et al., 2005a ) mitochondrial ATP synthesis in older adults. When expressing the rate of mitochondrial ATP synthesis relative to mitochondrial content there remains a deficit in older adults suggesting that there is not only a reduction in mitochon- drial protein content but also mitochondrial protein quality. These findings appear to be related to physical activity, as sedentary indi- viduals had lower in vivo mitochondrial function compared to ac- tive individuals ( Kent-Braun and Ng, 2000; Larsen et al., 2012 ). It is important to acknowledge that in aging human skeletal muscle, findings of mitochondrial dysfunction are highly equivocal and the disparity between studies is not well discussed. In Table 1 we pro-
vide potential confounding variables related to the characteristics of research participants (column A) as well as the use of various measurements of mitochondrial abundance or function (column B). Key differences exist when interpreting data since each mea- surement in Table 1
assesses different constituents of mitochon- drial abundance or function and each method presents key strengths and weaknesses as has been reviewed in detail previ- ously (
Lanza and Nair, 2010; Perry et al., 2013 ). One difference could be comparisons between content or maximal activities of en- zymes in the mitochondrial matrix (e.g., citrate synthase, bHAD) which are completely encoded by nuclear DNA vs. proteins in- volved in oxidative phosphorylation (e.g., cytochrome c oxidase, NADH) that are encoded by both nuclear and mitochondrial gen- omes. Although analysis of maximal mitochondrial energetics in vivo (i.e.,
31 P-MRS) and ex vivo (i.e., high-resolution respirome- try) are highly correlated ( Lanza et al., 2011 ), subtle discrepancies still exist between different approaches for measuring mitochon- drial function in vivo (basal vs. maximally stimulated) and ex vivo (ATP production vs. oxygen respiration; permeabilized fibers vs. isolated mitochondria). Also, sampling of human muscle tissue from various muscle groups consisting of different recruitment patterns and fiber type composition can create conflicting results between studies. These variables need to be recognized and ad- dressed to properly assess the true age-related phenotype. Glob- ally, when investigations utilize large sample sizes and rigorous control to avoid many of the confounding variables there appears to be an age-related decline in mitochondrial protein content, quality and function in the quadriceps femoris muscles. These data provide well-founded evidence for perturbations in mitochondrial health and connections to impaired functional capacity during sed- entary aging. Aerobic training is an effective exercise prescription to stimu- late markers of oxidative capacity as established in the 1960s ( Hol- loszy, 1967 ), when it was revealed that aerobic exercise of sufficient intensity increased mitochondrial enzyme activity in ani- mal models. Numerous other investigations have confirmed these results, however, few studies in humans have directly investigated if age influences exercise induced mitochondrial adaptations after the same exercise training program. From the few available stud- ies, it appears that mitochondrial molecular regulation and protein content are increased after 12–16 weeks of exercise training, inde- pendent of age, suggesting older individuals (<80 y) adapt favor- ably to exercise training ( Ghosh et al., 2011; Short et al., 2003 ). However, the influence of various exercise training programs (i.e., aerobic vs. resistance vs. concurrent training) on mitochondrial and skeletal muscle function (ex vivo or in vivo) has yet to be deter- mined and warrants investigation. Collectively, these data suggest that exercise can improve or prevent the loss of mitochondrial health during sedentary aging ( Fig. 2
). 3. Molecular Regulation of Aging Mitochondria The mitochondria consist of proteins encoded from both mito- chondrial (mtDNA) and nuclear DNA (nDNA). Although mtDNA contains just 27 genes that encode 13 proteins (all within the elec- tron transport chain), 2 ribosomal and 22 translational RNA, proper organelle biogenesis and function require input from both gen-
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