Mitochondrial Dynamics and Cardiac Function in Metabolic Disorders
Julieta Díaz-Juárez1 and Jorge Suarez2*
1Department of Pharmacology, Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México, México
2Department of Medicine, University of California, San Diego, USA
- *Corresponding Author:
- Jorge Suarez
Department of Medicine, University of California
San Diego, USA
Tel: (858) 534-9931
Fax: (858) 534-9932
E-mail: [email protected]
Received date: May 02, 2017; Accepted date: May 03, 2017; Published date: May 10, 2017
Citation: Díaz-Juárez J, Suarez J (2017) Mitochondrial Dynamics and Cardiac Function in Metabolic Disorders. J Metabolic Synd 6:e121. doi:
Copyright: © 2017 Díaz-Juárez J, et al. This is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Metabolic syndrome (MetS) is the name of a group of risk factors that can lead to develop several diseases including diabetes mellitus (DM). MetS is accompanied by central obesity, dyslipidemia, compromised fasting glucose, and hypertension . DM, especially type 2 diabetes (DM2), is a growing health care problem resulting in significant cardiovascular disease. Diabetic heart disease includes decreased cardiac contractile function in the absence of ischemia, termed diabetic cardiomyopathy (DCM). Most diabetic patients die of cardio-vascular disease. Cardiac Myocytes (CM) from diabetic type 1 (DM1) and (DM2) hearts exhibit abnormal cytosolic and sarcoplasmic reticulum (SR) calcium (Ca) handling, disturbed metabolic fuel flux, decreased mitochondrial (Mito) energetic efficiency and increased reactive oxygen species (ROS) production. Mitochondrial structural and dynamic abnormalities are also associated to DM. Dysfunctional Mito in DM2 may be due to impaired Mito dynamics, however, whether Mito dynamics contribute to MetS or DCM or are a therapeutic target for this disease have been only incompletely investigated. Recent work has highlighted the importance of mitochondrial morphological dynamics in cells and animal physiology. Because mitochondria constantly fuse and divide, an imbalance of these two processes dramatically alters overall mitochondrial morphology , and it is now clear that mitochondrial dynamics play important roles in mitochondrial function, including development, apoptosis, and functional complementation of mitochondrial DNA mutations by content mixing [3-9]. Fused networks of connected mitochondria may also facilitate the transmission of Ca2+ signals and membrane potential within cells [10,11]. Mito change their morphology between elongated, interconnected Mito networks (fusion) and a fragmented disconnected arrangement (fission). Dynamin proteins regulate Mito fusion (Mitofusins 1 and 2 (MFN1/2) , and optic atrophy1 (OPA1)) and fission (Dynamin-related protein 1 (DRP1) and mitochondrial fission protein1 (FIS1)) [3,13], and have been implicated in biological processes including metabolism, apoptosis, and autophagy, although the majority of studies have been confined to non-cardiac cells [14-22]. Changes in mitochondrial morphology are relevant to various aspects of cardiovascular biology and pathology. These include cardiac development, the response to ischemia-reperfusion injury, heart failure, diabetes mellitus, and apoptosis [14,16,18,20,23]. Furthermore, mitochondrial dynamics are important to maintain the mitochondrial membrane potential (ΔΨm) which in turn, is vital for mitochondrial calcium import and ATP production. In addition, we have highlighted the importance of normal mitochondrial calcium handling in MetS . It has been suggested that FIS1 recruits DRP1 from the cytosol to mitochondria for the fission reaction [25,26]. We have demonstrated that glucose concentrations that mimic hyperglycemia in humans increase mitochondrial fission in cardiac muscle cells . Increased Mito fission has been found in hearts of diabetic patients . We can postulate that DM-induced abnormalities of mitochondrial fission/ fusion dynamics can be reverted to towards normal despite persistent DM. We think that this can be achieved by the inhibition of specific fission-related proteins or activating fusion by overexpressing fusionrelated proteins in cardiac myocytes. We postulate that these specific rescue effects may lead to improved cardiac function and survival in DM. Tools to inhibit Mito fission have only been available recently. Three molecules have been studied in the last 5 years: Mdivi , P110 , and Dyanosore . Work has been performed in human disease animal models to test the beneficial effects of these compounds [32-35]. Mdivi is the most tested among these compounds. Mdivi interfere with the correct assemble of the GTPase domain of DRP1 inhibiting its enzymatic activity . Inhibiting Mito fission with Mdivi protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats [32,34]. Furthermore, Mdiviinhibition of excessive Mito fission after myocardial infarction prevents long-term cardiac dysfunction in mice , ischemia/reperfusion damage  and improves function in pressure overload-induced heart failure . In addition, Mdivi treatment protected against myocardial ischemia/reperfusion injury in diabetic mice. Unfortunately, beneficial effects of Mdivi treatment in MetS or diabetic cardiomyopathy have not been investigated. MetS leads to set the stage for serious problems. MetS double a patient risk of blood vessel and heart disease, which can lead to heart attacks and strokes. They increase to develop risk to develop diabetes by five times. Therefore, new and more effective therapeutics to prevent MetS complications must be developed. Inhibition of mitochondrial fission seems to be a promising therapeutic target that requires further investigation.
This Manuscript was supported by Grant from UC-MEXUS CONACYT (CN 15-1489).
- Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP (2010) Endothelial dysfunction in metabolic syndrome: prevalence, pathogenesis and management. Nutr Metab Cardiovasc Dis 20: 140-146.
- Bereiter-Hahn J and Vöth M (1994) Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27: 198-219.
- Chan DC (2006) Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 22: 79-99.
- Chen H and Chan DC (2005) Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet 14.
- Heath-Engel HM, Shore GC (2006) Mitochondrial membrane dynamics, cristae remodelling and apoptosis. Biochim Biophys Acta 1763: 549-560.
- Nakada K, Inoue K, Ono T, Isobe K, Ogura A, et al. (2001) Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med 7: 934-940.
- Ono T, Isobe K, Nakada K, Hayashi JI (2001) Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet 28: 272-275
- Scott SV, Cassidy-Stone A, Meeusen SL, Nunnari J (2003) Staying in aerobic shape: how the structural integrity of mitochondria and mitochondrial DNA is maintained. Curr Opin Cell Biol 15: 482-488.
- Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39: 359-407.
- Skulachev VP (2001) Mitochondrial filaments and clusters as intracellular power-transmitting cables. Trends Biochem Sci 26: 23-29.
- Szabadkai G, Simoni AM, Bianchi K, De Stefani D, Leo S, et al. (2006) Mitochondrial dynamics and Ca2+ signaling. See comment in PubMed Commons below Biochim Biophys Acta 1763: 442-449.
- Cipolat S, de Brito OM, Dal Zilio B, Scorrano L (2004) OPA1 requires mitofusin to promote mitochondrial fusion. Proc Natl Acad Sci USA 101: 15927-15932.
- Frazier AE, Kiu C, Stojanovski D, Hoogenraad NJ, Ryan MT (2006) Mitochondrial morphology and distribution in mammalian cells. Biol Chem 387: 1551-1558.
- Chen L, Gong Q, Stice JP, Knowlton AA (2009) Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res 84: 91-99.
- Chen H, Chan DC (2010) Physiological functions of mitochondrial fusion. Ann N Y Acad Sci 1201: 21-25.
- Makino A, Scott B, Dillmann W (2010) Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia 53: 1783-1794.
- Olichon A, Baricault L, Gas N, Guillou E, Valette A, et al. (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278: 7743-7746.
- Ong SB, Hausenloy DJ (2010) Mitochondrial morphology and cardiovascular disease. Cardiovasc Res 88: 16-29.
- Pich S, Bach D, Briones P, Liesa M, Camps M, et al. (1 June 2005) The Charcot- Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet 14: 1405-1415.
- Rosca M and Hoppel C (2009) New aspects of impaired mitochondrial function in heart failure. J Bioenerg Biomembr 41: 107-112.
- Yuan H, Gerencser AA, Liot G, Lipton SA, Ellisman M, et al. (2007) Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Cell Death Differ 14: 462-471.
- Yu T, Sheu SS, Robotham JL, Yoon Y (2008) Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res79: 341-351.
- Díaz-Juárez JSJ (2016) Metabolic Syndrome and Role of Mitochondrial Calcium Handling. J Metabolic Synd 5: e119.
- Mozdy AD, McCaffery JM, Shaw JM (2000) Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p. J Cell Biol 151: 367-380.
- Yoon Y, Krueger EW, Oswald B and McNiven MA (2003) The Mitochondrial Protein hFis1 Regulates Mitochondrial Fission in Mammalian Cells through an Interaction with the Dynamin-Like Protein DLP1. Mol Cell Biol 23: 5409-5420.
- Makino A, Suarez J, Gawlowski T, Han W, Wang H, et al. (2011) Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. Am J Physiol Regul Integr Comp Physiol 300: 1296-1302.
- Montaigne D, Marechal X, Coisne A, Debry N, Modine T, et al. (2014) Myocardial Contractile Dysfunction Is Associated With Impaired Mitochondrial Function and Dynamics in Type 2 Diabetic but Not in Obese Patients. Circulation 130: 554-564.
- Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, et al. (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14: 193-204.
- Qi X, Qvit N, Su YC, Mochly-Rosen D (2013) A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci 126: 789-802.
- Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, et al. (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10: 839-850.
- Qiu X, Cao L, Yang X, Zhao X, Liu X, et al. (2013) Role of mitochondrial fission in neuronal injury in pilocarpine-induced epileptic rats. Neuroscience 245: 157-165.
- Wappler EA, Institoris A, Dutta S, Katakam PV, Busija DW (2013) Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures. PloS one 8: e63206.
- Xie N, Wang C, Lian Y, Zhang H, Wu C, et al. (2013) A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett 545: 64-68.
- Zhang N, Wang S, Li Y, Che L, Zhao Q (2013) A selective inhibitor of Drp1, mdivi-1, acts against cerebral ischemia/reperfusion injury via an anti-apoptotic pathway in rats. Neurosci Lett 535: 104-109.
- Disatnik MH, Ferreira JCB, Campos JC, Gomes KS, Dourado PMM, et al. (2013) Acute Inhibition of Excessive Mitochondrial Fission After Myocardial Infarction Prevents Long-term Cardiac Dysfunction. J Am Heart Assoc 8: e000461.
- Sharp WW, Fang YH, Han M, Zhang HJ, Hong Z, et al. (2014) Dynaminrelated protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemiareperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. FASEB J 28: 316-326.
- Givvimani S, Munjal C, Tyagi N, Sen U, Metreveli N, et al. (2012) Mitochondrial division/mitophagy inhibitor (Mdivi) ameliorates pressure overload induced heart failure. PloS one 7: e32388.
- Ding M, Dong Q, Liu Z, Liu Z, Qu Y, et al. (2017) Inhibition of dynamin-related protein 1 protects against myocardial ischemia–reperfusion injury in diabetic mice. Cardiovasc Diabetol 16: 19.