Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission

Kensuke Tsushima; Heiko Bugger; Adam R Wende; Jamie Soto; Gregory A Jenson; Austin R Tor; Rose McGlauflin; Helena C Kenny; Yuan Zhang; Rhonda Souvenir; Xiao X Hu; Crystal L Sloan; Renata O Pereira; Vitor A Lira; Kenneth W Spitzer; Terry L Sharp; Kooresh I Shoghi; Genevieve C Sparagna; Eva A Rog-Zielinska; Peter Kohl; Oleh Khalimonchuk; Jean E Schaffer; E Dale Abel

doi:10.1161/CIRCRESAHA.117.311307

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Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission

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Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission

Kensuke Tsushima, Heiko Bugger, Adam R Wende, Jamie Soto, Gregory A Jenson, Austin R Tor, Rose McGlauflin, Helena C Kenny, Yuan Zhang, Rhonda Souvenir, …

Circulation research, Vol.122(1), pp.58-73

01/05/2018

DOI: 10.1161/CIRCRESAHA.117.311307

PMCID: PMC5756120

PMID: 29092894

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Abstract

Cardiac lipotoxicity, characterized by increased uptake, oxidation, and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes mellitus. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood. To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. Using a transgenic mouse model of cardiac lipotoxicity overexpressing ACSL1 (long-chain acyl-CoA synthetase 1) in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation in isolated mitochondria. Mitochondrial morphological changes and elevated ROS generation are also observed in palmitate-treated neonatal rat ventricular cardiomyocytes. Palmitate exposure to neonatal rat ventricular cardiomyocytes initially activates mitochondrial respiration, coupled with increased mitochondrial polarization and ATP synthesis. However, long-term exposure to palmitate (>8 hours) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. Mechanistically, lipid-induced changes in mitochondrial redox status increased mitochondrial fission by increased ubiquitination of AKAP121 (A-kinase anchor protein 121) leading to reduced phosphorylation of DRP1 (dynamin-related protein 1) at Ser637 and altered proteolytic processing of OPA1 (optic atrophy 1). Scavenging mitochondrial ROS restored mitochondrial morphology in vivo and in vitro. Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.

A Kinase Anchor Proteins - metabolism

Animals

Animals, Newborn

Cells, Cultured

Dynamins - metabolism

Isolated Heart Preparation - methods

Mice

Mice, Inbred C57BL

Mice, Transgenic

Mitochondrial Dynamics - physiology

Myocytes, Cardiac - metabolism

Myocytes, Cardiac - pathology

Optic Atrophy, Autosomal Dominant - metabolism

Protein Processing, Post-Translational - physiology

Rats

Rats, Wistar

Reactive Oxygen Species - metabolism

Details

Title: Subtitle: Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission
Creators: Kensuke Tsushima - University of Iowa, Internal Medicine
Heiko Bugger - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Adam R Wende - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Jamie Soto - University of Iowa, Internal Medicine
Gregory A Jenson - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Austin R Tor - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Rose McGlauflin - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Helena C Kenny - University of Iowa, Internal Medicine
Yuan Zhang - University of Iowa, Endocrinology and Metabolism
Rhonda Souvenir - University of Iowa, Endocrinology and Metabolism
Xiao X Hu - University of Iowa
Crystal L Sloan - University of Iowa
Renata O Pereira - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Vitor A Lira - University of Iowa, Health and Human Physiology
Kenneth W Spitzer - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Terry L Sharp - Washington University in St. Louis
Kooresh I Shoghi - Washington University in St. Louis
Genevieve C Sparagna - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Eva A Rog-Zielinska - University of Freiburg
Peter Kohl - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Oleh Khalimonchuk - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
Jean E Schaffer - From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.)
E Dale Abel - University of Iowa, Internal Medicine
Resource Type: Journal article
Publication Details: Circulation research, Vol.122(1), pp.58-73
DOI: 10.1161/CIRCRESAHA.117.311307
PMID: 29092894
PMCID: PMC5756120
ISSN: 0009-7330
eISSN: 1524-4571
Grant note: R01 DK064989 / NIDDK NIH HHS T32 HL007344 / NHLBI NIH HHS R37 HL042873 / NHLBI NIH HHS R01 HL108379 / NHLBI NIH HHS U54 DK110858 / NIDDK NIH HHS U01 HL087947 / NHLBI NIH HHS R01 HL127764 / NHLBI NIH HHS FS/15/3/31047 / British Heart Foundation P20 HL113444 / NHLBI NIH HHS S10 RR024761 / NCRR NIH HHS S10 RR025439 / NCRR NIH HHS
Language: English
Date published: 01/05/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Dental Research; Endocrinology and Metabolism; Health and Human Physiology; Internal Medicine
Record Identifier: 9984024518102771

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