Advertisement

Mitochondrial regulation of diabetic vascular disease: an emerging opportunity

  • Michael E. Widlansky
    Correspondence
    Reprint request: Michael E. Widlansky Division of Cardiovascular Medicine, Medicine, and Pharmacology, Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI 53226.
    Affiliations
    Department of Medicine, Division of Cardiovascular Medicine and Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin
    Search for articles by this author
  • R. Blake Hill
    Affiliations
    Department of Biochemisty, Medical College of Wisconsin, Milwaukee, Wisconsin
    Search for articles by this author
Published:August 03, 2018DOI:https://doi.org/10.1016/j.trsl.2018.07.015
      Diabetes-related vascular complication rates remain unacceptably high despite guideline-based medical therapies that are significantly more effective in individuals without diabetes. This critical gap represents an opportunity for researchers and clinicians to collaborate on targeting mechanisms and pathways that specifically contribute to vascular pathology in patients with diabetes mellitus. Dysfunctional mitochondria producing excessive mitochondrial reactive oxygen species (mtROS) play a proximal cell-signaling role in the development of vascular endothelial dysfunction in the setting of diabetes. Targeting the mechanisms of production of mtROS or mtROS themselves represents an attractive method to reduce the prevalence and severity of diabetic vascular disease. This review focuses on the role of mitochondria in the development of diabetic vascular disease and current developments in methods to improve mitochondrial health to improve vascular outcomes in patients with DM.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ford ES
        • Ajani UA
        • Croft JB
        • et al.
        Explaining the decrease in U.S. deaths from coronary disease, 1980-2000.
        N Engl J Med. 2007; 356: 2388-2398
        • Gregg EW
        • Li Y
        • Wang J
        • et al.
        Changes in diabetes-related complications in the United States, 1990-2010.
        N Engl J Med. 2014; 370: 1514-1523
        • Gross JL
        • de Azevedo MJ
        • Silveiro SP
        • Canani LH
        • Caramori ML
        • Zelmanovitz T
        Diabetic nephropathy: diagnosis, prevention, and treatment.
        Diabetes Care. 2005; 28: 164-176
        • Boulton AJ
        • Vinik AI
        • Arezzo JC
        • et al.
        Diabetic neuropathies: a statement by the American Diabetes Association.
        Diabetes Care. 2005; 28: 956-962
        • Prevention CfDCa
        National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States.
        US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA2011
        • Sun J
        • Pu Y
        • Wang P
        • et al.
        TRPV1-mediated UCP2 upregulation ameliorates hyperglycemia-induced endothelial dysfunction.
        Cardiovasc Diabetol. 2013; 12: 69
        • Widlansky ME
        • Gokce N
        • Keaney Jr., JF
        • Vita JA
        The clinical implications of endothelial dysfunction.
        J Am Coll Cardiol. 2003; 42: 1149-1160
        • Kitta Y
        • Obata JE
        • Nakamura T
        • et al.
        Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease.
        J Am Coll Cardiol. 2009; 53: 323-330
        • Johnstone MT
        • Creager SJ
        • Scales KM
        • Cusco JA
        • Lee BK
        • Creager MA
        Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.
        Circulation. 1993; 88: 2510-2516
        • Williams SB
        • Cusco JA
        • Roddy MA
        • Johnstone MT
        • Creager MA
        Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus.
        J Am Coll Cardiol. 1996; 27: 567-574
        • Williams SB
        • Goldfine AB
        • Timimi FK
        • et al.
        Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo.
        Circulation. 1998; 97: 1695-1701
        • Kizhakekuttu TJ
        • Wang J
        • Dharmashankar K
        • et al.
        Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans.
        Arterioscler Thromb Vasc Biol. 2012; 32: 2531-2539
        • Wang J
        • Alexanian A
        • Ying R
        • et al.
        Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochondrial oxidative stress: role for AMP kinase.
        Arterioscler Thromb Vasc Biol. 2012; 32: 712-720
        • El-Osta A
        • Brasacchio D
        • Yao D
        • et al.
        Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia.
        J Exp Med. 2008; 205: 2409-2417
        • Brownlee M
        Biochemistry and molecular cell biology of diabetic complications.
        Nature. 2001; 414: 813-820
        • Altschul R.
        Endothelium: its development, morphology, function, and pathology.
        Macmillan, New York, NY1954
        • Vita JA
        • Keaney Jr., JF
        Endothelial function: a barometer for cardiovascular risk?.
        Circulation. 2002; 106: 640-642
        • Flammer AJ
        • Anderson T
        • Celermajer DS
        • et al.
        The assessment of endothelial function: from research into clinical practice.
        Circulation. 2012; 126: 753-767
        • Moreno PR
        • Murcia AM
        • Palacios IF
        • et al.
        Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus.
        Circulation. 2000; 102: 2180-2184
        • Stone GW
        • Maehara A
        • Lansky AJ
        • et al.
        A prospective natural-history study of coronary atherosclerosis.
        N Engl J Med. 2011; 364: 226-235
        • Marso SP
        • Mercado N
        • Maehara A
        • et al.
        Plaque composition and clinical outcomes in acute coronary syndrome patients with metabolic syndrome or diabetes.
        JACC Cardiovasc Imaging. 2012; 5: S42-S52
        • Pajunen P
        • Taskinen MR
        • Nieminen MS
        • Syvanne M
        Angiographic severity and extent of coronary artery disease in patients with type 1 diabetes mellitus.
        Am J Cardiol. 2000; 86: 1080-1085
        • The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus
        The Diabetes Control and Complications Trial Research Group.
        N Engl J Med. 1993; 329: 977-986
        • Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
        UK Prospective Diabetes Study (UKPDS) Group.
        Lancet. 1998; 352: 837-853
        • Abraira C
        • Colwell JA
        • Nuttall FQ
        • et al.
        Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans affairs cooperative study in type II diabetes.
        Diabetes Care. 1995; 18: 1113-1123
        • Wright RJ
        • Newby DE
        • Stirling D
        • Ludlam CA
        • Macdonald IA
        • Frier BM
        Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes.
        Diabetes Care. 2010; 33: 1591-1597
        • Ceriello A
        • Novials A
        • Ortega E
        • et al.
        Evidence that hyperglycemia after recovery from hypoglycemia worsens endothelial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type 1 diabetes.
        Diabetes. 2012; 61: 2993-2997
        • Gogitidze JN
        • Hedrington MS
        • Briscoe VJ
        • Tate DB
        • Ertl AC
        • Davis SN
        Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals.
        Diabetes Care. 2010; 33: 1529-1535
        • Chittari MV
        • McTernan P
        • Bawazeer N
        • et al.
        Impact of acute hyperglycaemia on endothelial function and retinal vascular reactivity in patients with Type 2 diabetes.
        Diabetes Med. 2011; 28: 450-454
        • Kawano H
        • Motoyama T
        • Hirashima O
        • et al.
        Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery.
        J Am Coll Cardiol. 1999; 34: 146-154
        • Gimenez M
        • Gilabert R
        • Monteagudo J
        • et al.
        Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes.
        Diabetes Care. 2011; 34: 198-203
        • Pena AS
        • Couper JJ
        • Harrington J
        • et al.
        Hypoglycemia, but not glucose variability, relates to vascular function in children with type 1 diabetes.
        Diabetes Technol Ther. 2012; 14: 457-462
        • Kim F
        • Tysseling KA
        • Rice J
        • et al.
        Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKK{beta}.
        Arterioscler Thromb Vasc Biol. 2005;
        • Azekoshi Y
        • Yasu T
        • Watanabe S
        • et al.
        Free fatty acid causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells.
        Hypertension. 2010; 56: 136-142
        • Ghosh A
        • Gao L
        • Thakur A
        • Siu PM
        • Lai CWK
        Role of free fatty acids in endothelial dysfunction.
        J Biomed Sci. 2017; 24: 50
        • Mathew M
        • Tay E
        • Cusi K
        Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects.
        Cardiovasc Diabetol. 2010; 9: 9
        • Umpierrez GE
        • Smiley D
        • Robalino G
        • et al.
        Intravenous intralipid-induced blood pressure elevation and endothelial dysfunction in obese African-Americans with type 2 diabetes.
        J Clin Endocrinol Metab. 2009; 94: 609-614
        • de Jongh RT
        • Serne EH
        • IJzerman RG
        • de Vries G
        • Stehouwer CD
        Free fatty acid levels modulate microvascular function: relevance for obesity-associated insulin resistance, hypertension, and microangiopathy.
        Diabetes. 2004; 53: 2873-2882
        • Alvarez S
        • Valdez LB
        • Zaobornyj T
        • Boveris A
        Oxygen dependence of mitochondrial nitric oxide synthase activity.
        Biochem Biophys Res Commun. 2003; 305: 771-775
        • Wittenberg BA
        • Wittenberg JB
        Transport of oxygen in muscle.
        Annu Rev Physiol. 1989; 51: 857-878
        • Orrenius S
        • Gogvadze V
        • Zhivotovsky B
        Mitochondrial oxidative stress: implications for cell death.
        Annu Rev Pharmacol Toxicol. 2007; 47: 143-183
        • Giorgio M
        • Migliaccio E
        • Orsini F
        • et al.
        Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis.
        Cell. 2005; 122: 221-233
        • Murphy MP
        How mitochondria produce reactive oxygen species.
        Biochem J. 2009; 417: 1-13
        • Widlansky ME
        • Gutterman DD
        Regulation of endothelial function by mitochondrial reactive oxygen species.
        Antioxid Redox Signal. 2011; 15: 1517-1530
        • Cadenas E
        • Davies KJ
        Mitochondrial free radical generation, oxidative stress, and aging.
        Free Radic Biol Med. 2000; 29: 222-230
        • Zhang L
        • Yu L
        • Yu CA
        Generation of superoxide anion by succinate-cytochrome c reductase from bovine heart mitochondria.
        J Biol Chem. 1998; 273: 33972-33976
        • Culic O
        • Gruwel ML
        • Schrader J
        Energy turnover of vascular endothelial cells.
        Am J Physiol. 1997; 273 (C205–C13)
        • Widder JD
        • Fraccarollo D
        • Galuppo P
        • et al.
        Attenuation of angiotensin II-induced vascular dysfunction and hypertension by overexpression of Thioredoxin 2.
        Hypertension. 2009; 54: 338-344
        • Pueyo ME
        • Gonzalez W
        • Nicoletti A
        • Savoie F
        • Arnal JF
        • Michel JB
        Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress.
        Arterioscler Thromb Vasc Biol. 2000; 20: 645-651
        • Bienert GP
        • Moller AL
        • Kristiansen KA
        • et al.
        Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes.
        J Biol Chem. 2007; 282: 1183-1192
        • Calamita G
        • Ferri D
        • Gena P
        • et al.
        The inner mitochondrial membrane has aquaporin-8 water channels and is highly permeable to water.
        J Biol Chem. 2005; 280: 17149-17153
        • Burwell LS
        • Nadtochiy SM
        • Tompkins AJ
        • Young S
        • Brookes PS
        Direct evidence for S-nitrosation of mitochondrial complex I.
        Biochem J. 2006; 394: 627-634
        • Cassina A
        • Radi R
        Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport.
        Arch Biochem Biophys. 1996; 328: 309-316
        • Clementi E
        • Brown GC
        • Feelisch M
        • Moncada S
        Persistent inhibition of cell respiration by nitric oxide: crucial role ofS-nitrosylation of mitochondrial complex I and protective action of glutathione.
        Proc Natl Acad Sci U S A. 1998; 95: 7631-7636
        • Dahm CC
        • Moore K
        • Murphy MP
        Persistent S-nitrosation of complex I and other mitochondrial membrane proteins by S-nitrosothiols but not nitric oxide or peroxynitrite: implications for the interaction of nitric oxide with mitochondria.
        J Biol Chem. 2006; 281: 10056-10065
        • Miura H
        • Bosnjak JJ
        • Ning G
        • Saito T
        • Miura M
        • Gutterman DD
        Role for hydrogen peroxide in flow-induced dilation of human coronary arterioles.
        Circa Res. 2003; 92: e31-e40
        • Phillips SA
        • Haltom OA
        • Gutterman DD
        The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD.
        Am J Physiol Heart Circa Physiol. 2007; 292: H93-100
        • Durand MJ
        • Dharmashankar K
        • Bian JT
        • et al.
        Acute exertion elicits a H2O2-dependent vasodilator mechanism in the microvasculature of exercise-trained but not sedentary adults.
        Hypertension. 2015; 65: 140-145
        • Nishikawa T
        • Edelstein D
        • Du XL
        • et al.
        Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage.
        Nature. 2000; 404: 787-790
        • Du XL
        • Edelstein D
        • Rossetti L
        • et al.
        Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation.
        Proc Natl Acad Sci U S A. 2000; 97: 12222-12226
        • Keating ST
        • El-Osta A
        Chromatin modifications associated with diabetes.
        J Cardiovasc Transl Res. 2012; 5: 399-412
        • Pirola L
        • Balcerczyk A
        • Tothill RW
        • et al.
        Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells.
        Genome Res. 2011; 21: 1601-1615
        • Nathan DM
        • Cleary PA
        • Backlund JY
        • et al.
        Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
        N Engl J Med. 2005; 353: 2643-2653
        • Petersen KF
        • Dufour S
        • Befroy D
        • Garcia R
        • Shulman GI
        Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes.
        N Engl J Med. 2004; 350: 664-671
        • Gareus R
        • Kotsaki E
        • Xanthoulea S
        • et al.
        Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis.
        Cell Metab. 2008; 8: 372-383
        • Ristow M
        • Schmeisser K
        Mitohormesis: promoting health and lifespan by increased levels of Reactive Oxygen Species (ROS).
        Dose Response. 2014; 12: 288-341
        • Gendron ME
        • Thorin-Trescases N
        • Mamarbachi AM
        • et al.
        Time-dependent beneficial effect of chronic polyphenol treatment with catechin on endothelial dysfunction in aging mice.
        Dose Response. 2012; 10: 108-119
        • Ristow M
        • Zarse K
        • Oberbach A
        • et al.
        Antioxidants prevent health-promoting effects of physical exercise in humans.
        Proc Natl Acad Sci U S A. 2009; 106: 8665-8670
        • Tanner MJ
        • Wang J
        • Ying R
        • et al.
        Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles.
        Am J Physiol Heart Circ Physiol. 2017; 312 (H515–H27)
        • Gioscia-Ryan RA
        • LaRocca TJ
        • Sindler AL
        • Zigler MC
        • Murphy MP
        • Seals DR
        Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice.
        J Physiol. 2014; 592: 2549-2561
        • Graham D
        • Huynh NN
        • Hamilton CA
        • et al.
        Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy.
        Hypertension. 2009; 54: 322-328
        • Park SY
        • Kwon OS
        • Andtbacka RHI
        • et al.
        Age-related endothelial dysfunction in human skeletal muscle feed arteries: the role of free radicals derived from mitochondria in the vasculature.
        Acta Physiol (Oxf). 2018; 1: 222
        • Rossman MJ
        • Santos-Parker JR
        • Steward CAC
        • et al.
        Chronic supplementation with a Mitochondrial Antioxidant (MitoQ) improves vascular function in healthy older adults.
        Hypertension. 2018;
        • Mosca L
        • Appel LJ
        • Benjamin EJ
        • et al.
        Evidence-based guidelines for cardiovascular disease prevention in women.
        Circulation. 2004; 109: 672-693
        • Gibbons RJ
        • Abrams J
        • Chatterjee K
        • et al.
        ACC/AHA 2002 guideline update for the management of patients with chronic stable angina–summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina).
        Circulation. 2003; 107: 149-158
        • Warnholtz A
        • Munzel T
        Why do antioxidants fail to provide clinical benefit?.
        Curr Control Trials Cardiovasc Med. 2000; 1: 38-40
        • Wang W
        • Karamanlidis G
        • Tian R
        Novel targets for mitochondrial medicine.
        Sci Transl Med. 2016; 8 (326rv3)
        • Sweet IR
        • Gilbert M
        • Maloney E
        • Hockenbery DM
        • Schwartz MW
        • Kim F
        Endothelial inflammation induced by excess glucose is associated with cytosolic glucose 6-phosphate but not increased mitochondrial respiration.
        Diabetologia. 2009; 52: 921-931
        • Koziel A
        • Woyda-Ploszczyca A
        • Kicinska A
        • Jarmuszkiewicz W
        The influence of high glucose on the aerobic metabolism of endothelial EA.hy926 cells.
        Pflugers Arch. 2012; 464: 657-669
        • Scott I
        • Webster BR
        • Li JH
        • Sack MN
        Identification of a molecular component of the mitochondrial acetyltransferase programme: a novel role for GCN5L1.
        Biochem J. 2012; 443: 655-661
        • Baeza J
        • Smallegan MJ
        • Denu JM
        Site-specific reactivity of nonenzymatic lysine acetylation.
        ACS Chem Biol. 2015; 10: 122-128
        • Kumar S
        • Kim YR
        • Vikram A
        • et al.
        Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes–induced vascular oxidative stress and endothelial dysfunction.
        Proc Natl Acad Sci U S A. 2017; 114: 1714-1719
        • Zhou S
        • Chen HZ
        • Wan YZ
        • et al.
        Repression of P66Shc expression by SIRT1 contributes to the prevention of hyperglycemia-induced endothelial dysfunction.
        Circ Res. 2011; 109: 639-648
        • Cai W
        • He JC
        • Zhu L
        • Chen X
        • Striker GE
        • Vlassara H
        AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation.
        Am J Physiol Cell Physiol. 2008; 294: C145-C152
        • Guo J
        • Gertsberg Z
        • Ozgen N
        • Steinberg SF
        p66Shc links alpha1-adrenergic receptors to a reactive oxygen species-dependent AKT-FOXO3A phosphorylation pathway in cardiomyocytes.
        Circ Res. 2009; 104: 660-669
        • Paneni F
        • Mocharla P
        • Akhmedov A
        • et al.
        Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes.
        Circ Res. 2012; 111: 278-289
        • Zhang H
        • Zhang J
        • Ungvari Z
        • Zhang C
        Resveratrol improves endothelial function: role of TNF{alpha} and vascular oxidative stress.
        Arterioscler Thromb Vasc Biol. 2009; 29: 1164-1171
        • Zhang QJ
        • Wang Z
        • Chen HZ
        • et al.
        Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice.
        Cardiovasc Res. 2008; 80: 191-199
        • Chen ML
        • Yi L
        • Jin X
        • et al.
        Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway.
        Autophagy. 2013; 9: 2033-2045
        • Arunachalam G
        • Yao H
        • Sundar IK
        • Caito S
        • Rahman I
        SIRT1 regulates oxidant- and cigarette smoke-induced eNOS acetylation in endothelial cells: Role of resveratrol.
        Biochem Biophys Res Commun. 2010; 393: 66-72
        • Brunet A
        • Sweeney LB
        • Sturgill JF
        • et al.
        Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.
        Science. 2004; 303: 2011-2015
        • Mattagajasingh I
        • Kim CS
        • Naqvi A
        • et al.
        SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase.
        Proc Natl Acad Sci U S A. 2007; 104: 14855-14860
        • Pollack RM
        • Barzilai N
        • Anghel V
        • et al.
        Resveratrol improves vascular function and mitochondrial number but not glucose metabolism in older adults.
        J Gerontol A Biol Sci Med Sci. 2017; 72: 1703-1709
        • Ma S
        • Feng J
        • Zhang R
        • et al.
        SIRT1 activation by resveratrol alleviates cardiac dysfunction via mitochondrial regulation in diabetic cardiomyopathy mice.
        Oxid Med Cell Longev. 2017; 20174602715
        • Liu K
        • Zhou R
        • Wang B
        • Mi MT
        Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials.
        Am J Clin Nutr. 2014; 99: 1510-1519
        • Haigis MC
        • Sinclair DA
        Mammalian sirtuins: biological insights and disease relevance.
        Annu Rev Pathol. 2010; 5: 253-295
        • Imai S.
        “Clocks” in the NAD World: NAD as a metabolic oscillator for the regulation of metabolism and aging.
        Biochim Biophys Acta. 2010; 1804: 1584-1590
        • Yoshino J
        • Baur JA
        • Imai SI
        NAD(+) intermediates: the biology and therapeutic potential of NMN and NR.
        Cell Metab. 2018; 27: 513-528
        • Yoshino J
        • Mills KF
        • Yoon MJ
        • Imai S
        Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice.
        Cell Metab. 2011; 14: 528-536
        • Canto C
        • Houtkooper RH
        • Pirinen E
        • et al.
        The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity.
        Cell Metab. 2012; 15: 838-847
        • Lee HJ
        • Hong YS
        • Jun W
        • Yang SJ
        Nicotinamide riboside ameliorates hepatic metaflammation by modulating NLRP3 inflammasome in a rodent model of Type 2 Diabetes.
        J Med Food. 2015; 18: 1207-1213
        • de Picciotto NE
        • Gano LB
        • Johnson LC
        • et al.
        Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.
        Aging Cell. 2016; 15: 522-530
        • Chen MP
        • Chung FM
        • Chang DM
        • et al.
        Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus.
        J Clin Endocrinol Metab. 2006; 91: 295-299
        • Romacho T
        • Villalobos LA
        • Cercas E
        • Carraro R
        • Sanchez-Ferrer CF
        • Peiro C
        Visfatin as a novel mediator released by inflamed human endothelial cells.
        PLoS One. 2013; 8: e78283
        • Wang P
        • Xu TY
        • Guan YF
        • Su DF
        • Fan GR
        • Miao CY
        Perivascular adipose tissue-derived visfatin is a vascular smooth muscle cell growth factor: role of nicotinamide mononucleotide.
        Cardiovasc Res. 2009; 81: 370-380
        • Chen Y
        • Pitzer AL
        • Li X
        • Li PL
        • Wang L
        • Zhang Y
        Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: role of HMGB1.
        J Cell Mol Med. 2015; 19: 2715-2727
        • Lee WJ
        • Wu CS
        • Lin H
        • et al.
        Visfatin-induced expression of inflammatory mediators in human endothelial cells through the NF-kappaB pathway.
        Int J Obes (Lond). 2009; 33: 465-472
        • Kim SR
        • Bae YH
        • Bae SK
        • et al.
        Visfatin enhances ICAM-1 and VCAM-1 expression through ROS-dependent NF-kappaB activation in endothelial cells.
        Biochim Biophys Acta. 2008; 1783: 886-895
        • Takebayashi K
        • Suetsugu M
        • Wakabayashi S
        • Aso Y
        • Inukai T
        Association between plasma visfatin and vascular endothelial function in patients with type 2 diabetes mellitus.
        Metabolism. 2007; 56: 451-458
        • Yilmaz MI
        • Saglam M
        • Carrero JJ
        • et al.
        Serum visfatin concentration and endothelial dysfunction in chronic kidney disease.
        Nephrol Dial Transplant. 2008; 23: 959-965
        • Dahl TB
        • Yndestad A
        • Skjelland M
        • et al.
        Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization.
        Circulation. 2007; 115: 972-980
        • Garten A
        • Schuster S
        • Penke M
        • Gorski T
        • de Giorgis T
        • Kiess W
        Physiological and pathophysiological roles of NAMPT and NAD metabolism.
        Nat Rev Endocrinol. 2015; 11: 535-546
        • Hara N
        • Yamada K
        • Shibata T
        • Osago H
        • Tsuchiya M
        Nicotinamide phosphoribosyltransferase/visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma.
        PLoS One. 2011; 6: e22781
        • Wang G
        • Han T
        • Nijhawan D
        • et al.
        P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage.
        Cell. 2014; 158: 1324-1334
        • Choi SE
        • Fu T
        • Seok S
        • et al.
        Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT.
        Aging Cell. 2013; 12: 1062-1072
        • Szeto HH
        • Liu S
        • Soong Y
        • Birk AV
        Improving mitochondrial bioenergetics under ischemic conditions increases warm ischemia tolerance in the kidney.
        Am J Physiol Renal Physiol. 2015; 308: F11-F21
        • Gebert N
        • Joshi AS
        • Kutik S
        • et al.
        Mitochondrial cardiolipin involved in outer-membrane protein biogenesis: implications for Barth syndrome.
        Curr Biol. 2009; 19: 2133-2139
        • Tatsuta T
        • Langer T
        Intramitochondrial phospholipid trafficking.
        Biochim Biophys Acta. 2017; 1862: 81-89
        • Dudek J
        Role of cardiolipin in mitochondrial signaling pathways.
        Front Cell Dev Biol. 2017; 5: 90
        • Han X
        • Yang J
        • Yang K
        • Zhao Z
        • Abendschein DR
        • Gross RW
        Alterations in myocardial cardiolipin content and composition occur at the very earliest stages of diabetes: a shotgun lipidomics study.
        Biochemistry. 2007; 46: 6417-6428
        • Petrosillo G
        • Matera M
        • Moro N
        • Ruggiero FM
        • Paradies G
        Mitochondrial complex I dysfunction in rat heart with aging: critical role of reactive oxygen species and cardiolipin.
        Free Radic Biol Med. 2009; 46: 88-94
        • Hagen TM
        • Ingersoll RT
        • Wehr CM
        • et al.
        Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity.
        Proc Natl Acad Sci USA. 1998; 95: 9562-9566
        • Schlame M
        • Rua D
        • Greenberg ML
        The biosynthesis and functional role of cardiolipin.
        Prog Lipid Res. 2000; 39: 257-288
        • Widlansky ME
        • Wang J
        • Shenouda SM
        • et al.
        Altered mitochondrial membrane potential, mass, and morphology in the mononuclear cells of humans with type 2 diabetes.
        Transl Res. 2010; 156: 15-25
        • Birk AV
        • Liu S
        • Soong Y
        • et al.
        The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin.
        J Am Soc Nephrol. 2013; 24: 1250-1261
        • Szeto HH
        Cell-permeable, mitochondrial-targeted, peptide antioxidants.
        AAPS J. 2006; 8: E277-E283
        • Birk AV
        • Chao WM
        • Bracken C
        • Warren JD
        • Szeto HH
        Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis.
        Br J Pharmacol. 2014; 171: 2017-2028
        • Zhang M
        • Zhao H
        • Cai J
        • et al.
        Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet.
        PLoS One. 2017; 12e0185688
        • Alam NM
        • WCt Mills
        • Wong AA
        • Douglas RM
        • Szeto HH
        • Prusky GT
        A mitochondrial therapeutic reverses visual decline in mouse models of diabetes.
        Dis Model Mech. 2015; 8: 701-710
        • Huang J
        • Li X
        • Li M
        • et al.
        Mitochondria-targeted antioxidant peptide SS31 protects the retinas of diabetic rats.
        Curr Mol Med. 2013; 13: 935-945
        • Blum A
        • Hathaway L
        • Mincemoyer R
        • et al.
        Effects of oral L-arginine on endothelium-dependent vasodilation and markers of inflammation in healthy postmenopausal women.
        J Am Coll Cardiol. 2000; 35: 271-276
        • Daubert MA
        • Yow E
        • Dunn G
        • et al.
        Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide.
        Circ Heart Fail. 2017; 10: e004389https://doi.org/10.1161/CIRCHEARTFAILURE.117.004389
        • Gibson CM
        • Giugliano RP
        • Kloner RA
        • et al.
        EMBRACE STEMI study: a phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention.
        Eur Heart J. 2016; 37: 1296-1303
        • Hollenbeck PJ
        • Saxton WM
        The axonal transport of mitochondria.
        J Cell Sci. 2005; 118: 5411-5419
        • Chang CR
        • Blackstone C
        Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1.
        Ann N Y Acad Sci. 2010; 1201: 34-39
        • Chen H
        • Chan DC
        Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases.
        Hum Mol Genet. 2009; 18 (R169–R76)
        • Chan DC.
        Fusion and fission: interlinked processes critical for mitochondrial health.
        Annu Rev Genet. 2012; 46: 265-287
        • Nakada K
        • Inoue K
        • Ono T
        • et al.
        Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA.
        Nat Med. 2001; 7: 934-940
        • Youle RJ
        • van der Bliek AM
        Mitochondrial fission, fusion, and stress.
        Science. 2012; 337: 1062-1065
        • Zhao J
        • Lendahl U
        • Nister M
        Regulation of mitochondrial dynamics: convergences and divergences between yeast and vertebrates.
        Cell Mol Life Sci. 2013; 70: 951-976
        • Twig G
        • Elorza A
        • Molina AJ
        • et al.
        Fission and selective fusion govern mitochondrial segregation and elimination by autophagy.
        EMBO J. 2008; 27: 433-446
        • Shenouda SM
        • Widlansky ME
        • Chen K
        • et al.
        Alterered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus.
        Circulation. 2011; 124: 444-453
        • Shenouda SM
        • Widlansky ME
        • Chen K
        • et al.
        Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus.
        Circulation. 2011; 124: 444-453
        • Smirnova E
        • Griparic L
        • Shurland DL
        • van der Bliek AM
        Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells.
        Mol Biol Cell. 2001; 12: 2245-2256
        • Kim H
        • Scimia MC
        • Wilkinson D
        • et al.
        Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia.
        Mol Cell. 2011; 44: 532-544
        • Kumari S
        • Anderson L
        • Farmer S
        • Mehta SL
        • Li PA
        Hyperglycemia alters mitochondrial fission and fusion proteins in mice subjected to cerebral ischemia and reperfusion.
        Transl Stroke Res. 2012; 3: 296-304
        • Ciarlo L
        • Manganelli V
        • Garofalo T
        • et al.
        Association of fission proteins with mitochondrial raft-like domains.
        Cell Death Differ. 2010; 17: 1047-1058
        • Kaddour-Djebbar I
        • Choudhary V
        • Brooks C
        • et al.
        Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells.
        Int J Oncol. 2010; 36: 1437-1444
        • Yu T
        • Robotham JL
        • Yoon Y
        Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology.
        Proc Natl Acad Sci U S A. 2006; 103: 2653-2658
        • Diaz-Morales N
        • Rovira-Llopis S
        • Banuls C
        • et al.
        Are mitochondrial fusion and fission impaired in leukocytes of type 2 diabetic patients?.
        Antioxid Redox Signal. 2016; 25: 108-115
        • Cassidy-Stone A
        • Chipuk JE
        • Ingerman E
        • et al.
        Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization.
        Dev Cell. 2008; 14: 193-204
        • Li A
        • Zhang S
        • Li J
        • Liu K
        • Huang F
        • Liu B
        Metformin and resveratrol inhibit Drp1-mediated mitochondrial fission and prevent ER stress-associated NLRP3 inflammasome activation in the adipose tissue of diabetic mice.
        Mol Cell Endocrinol. 2016; 434: 36-47
        • Cahill TJ
        • Leo V
        • Kelly M
        • et al.
        Resistance of dynamin-related protein 1 oligomers to disassembly impairs mitophagy, resulting in myocardial inflammation and heart failure.
        J Biol Chem. 2016; 291: 25762
        • Bordt EA
        • Clerc P
        • Roelofs BA
        • et al.
        The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species.
        Dev Cell. 2017; 40 (e6): 583-594
        • Qi X
        • Qvit N
        • Su YC
        • Mochly-Rosen D
        A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity.
        J Cell Sci. 2013; 126: 789-802
        • Disatnik MH
        • Ferreira JC
        • Campos JC
        • et al.
        Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long-term cardiac dysfunction.
        J Am Heart Assoc. 2013; 2e000461
        • Coronado M
        • Fajardo G
        • Nguyen K
        • et al.
        Physiological mitochondrial fragmentation is a normal cardiac adaptation to increased energy demand.
        Circ Res. 2018; 122: 282-295
        • Chen C
        • Gao JL
        • Liu MY
        • et al.
        Mitochondrial fission inhibitors suppress endothelin-1-induced artery constriction.
        Cell Physiol Biochem. 2017; 42: 1802-1811
        • Cogliati S
        • Frezza C
        • Soriano ME
        • et al.
        Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency.
        Cell. 2013; 155: 160-171
        • Makino A
        • Scott BT
        • Dillmann WH
        Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes.
        Diabetologia. 2010; 53: 1783-1794
        • Hall AR
        • Burke N
        • Dongworth RK
        • Hausenloy DJ
        Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease.
        Br J Pharmacol. 2014; 171: 1890-1906
        • Liu N
        • Wu J
        • Zhang L
        • et al.
        Hydrogen sulphide modulating mitochondrial morphology to promote mitophagy in endothelial cells under high-glucose and high-palmitate.
        J Cell Mol Med. 2017; 21: 3190-3203
        • Sun R
        • Wang X
        • Liu Y
        • Xia M
        Dietary supplementation with fish oil alters the expression levels ofproteins governing mitochondrial dynamics and prevents high-fat diet-induced endothelial dysfunction.
        Br J Nutr. 2014; 112: 145-153
        • Yue W
        • Chen Z
        • Liu H
        • et al.
        A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30.
        Cell Res. 2014; 24: 482-496
        • Ikeda Y
        • Shirakabe A
        • Maejima Y
        • et al.
        Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress.
        Circ Res. 2015; 116: 264-278
        • Kageyama Y
        • Hoshijima M
        • Seo K
        • et al.
        Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain.
        EMBO J. 2014; 33: 2798-2813
        • Tian XY
        • Wong WT
        • Xu A
        • et al.
        Uncoupling protein-2 protects endothelial function in diet-induced obese mice.
        Circ Res. 2012; 110: 1211-1216
        • Bravo-San Pedro JM
        • Kroemer G
        • Galluzzi L
        Autophagy and mitophagy in cardiovascular disease.
        Circ Res. 2017; 120: 1812-1824
        • Corrado M
        • Mariotti FR
        • Trapani L
        • et al.
        Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis.
        EMBO J. 2016; 35: 1793-1809
        • Wu W
        • Xu H
        • Wang Z
        • et al.
        PINK1-Parkin-mediated mitophagy protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury.
        PLoS One. 2015; 10e0132499
        • Tang X
        • Luo YX
        • Chen HZ
        • Liu DP
        Mitochondria, endothelial cell function, and vascular diseases.
        Front Physiol. 2014; 5: 175
        • Kaplon RE
        • Hill SD
        • Bispham NZ
        • et al.
        Oral trehalose supplementation improves resistance artery endothelial function in healthy middle-aged and older adults.
        Aging (Albany NY). 2016; 8: 1167-1183
        • LaRocca TJ
        • Henson GD
        • Thorburn A
        • Sindler AL
        • Pierce GL
        • Seals DR
        Translational evidence that impaired autophagy contributes to arterial ageing.
        J Physiol. 2012; 590: 3305-3316
        • Collins J
        • Robinson C
        • Danhof H
        • et al.
        Dietary trehalose enhances virulence of epidemic Clostridium difficile.
        Nature. 2018; 553: 291-294