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 & 3 others Oleh Khalimonchuk, Jean E. Schaffer, E. Dale Abel

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Rationale: 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. Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. Methods and Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)58-73
Number of pages16
JournalCirculation Research
Volume122
Issue number1
DOIs
StatePublished - Jan 5 2018

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A Kinase Anchor Proteins
Autosomal Dominant Optic Atrophy
Mitochondrial Dynamics
Dynamins
Post Translational Protein Processing
Reactive Oxygen Species
Palmitates
Lipids
Cardiac Myocytes
Proteins
Coenzyme A Ligases
Reticulum
Acyl Coenzyme A
Carnitine
Ubiquitination
Mitochondrial Proteins
Cardiomyopathies
Transgenic Mice
Oxidation-Reduction
Diabetes Mellitus

Keywords

  • heart failure
  • metabolism
  • mitochondrial dynamics
  • oxidative stress
  • reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission. / Tsushima, Kensuke; Bugger, Heiko; Wende, Adam R.; Soto, Jamie; Jenson, Gregory A.; Tor, Austin R.; McGlauflin, Rose; Kenny, Helena C.; Zhang, Yuan; Souvenir, Rhonda; Hu, Xiao X.; Sloan, Crystal L.; Pereira, Renata O.; Lira, Vitor A.; Spitzer, Kenneth W.; Sharp, Terry L.; Shoghi, Kooresh I.; Sparagna, Genevieve C.; Rog-Zielinska, Eva A.; Kohl, Peter; Khalimonchuk, Oleh; Schaffer, Jean E.; Abel, E. Dale.

In: Circulation Research, Vol. 122, No. 1, 05.01.2018, p. 58-73.

Research output: Contribution to journalArticle

Tsushima, K, Bugger, H, Wende, AR, Soto, J, Jenson, GA, Tor, AR, McGlauflin, R, Kenny, HC, Zhang, Y, Souvenir, R, Hu, XX, Sloan, CL, Pereira, RO, Lira, VA, Spitzer, KW, Sharp, TL, Shoghi, KI, Sparagna, GC, Rog-Zielinska, EA, Kohl, P, Khalimonchuk, O, Schaffer, JE & Abel, ED 2018, 'Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission', Circulation Research, vol. 122, no. 1, pp. 58-73. https://doi.org/10.1161/CIRCRESAHA.117.311307
Tsushima, Kensuke ; Bugger, Heiko ; Wende, Adam R. ; Soto, Jamie ; Jenson, Gregory A. ; Tor, Austin R. ; McGlauflin, Rose ; Kenny, Helena C. ; Zhang, Yuan ; Souvenir, Rhonda ; Hu, Xiao X. ; Sloan, Crystal L. ; Pereira, Renata O. ; Lira, Vitor A. ; Spitzer, Kenneth W. ; Sharp, Terry L. ; Shoghi, Kooresh I. ; Sparagna, Genevieve C. ; Rog-Zielinska, Eva A. ; Kohl, Peter ; Khalimonchuk, Oleh ; Schaffer, Jean E. ; Abel, E. Dale. / Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission. In: Circulation Research. 2018 ; Vol. 122, No. 1. pp. 58-73.
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abstract = "Rationale: 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. Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. Methods and Results: 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. Conclusions: 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.",
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T1 - Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission

AU - Tsushima, Kensuke

AU - Bugger, Heiko

AU - Wende, Adam R.

AU - Soto, Jamie

AU - Jenson, Gregory A.

AU - Tor, Austin R.

AU - McGlauflin, Rose

AU - Kenny, Helena C.

AU - Zhang, Yuan

AU - Souvenir, Rhonda

AU - Hu, Xiao X.

AU - Sloan, Crystal L.

AU - Pereira, Renata O.

AU - Lira, Vitor A.

AU - Spitzer, Kenneth W.

AU - Sharp, Terry L.

AU - Shoghi, Kooresh I.

AU - Sparagna, Genevieve C.

AU - Rog-Zielinska, Eva A.

AU - Kohl, Peter

AU - Khalimonchuk, Oleh

AU - Schaffer, Jean E.

AU - Abel, E. Dale

PY - 2018/1/5

Y1 - 2018/1/5

N2 - Rationale: 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. Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. Methods and Results: 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. Conclusions: 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.

AB - Rationale: 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. Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. Methods and Results: 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. Conclusions: 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.

KW - heart failure

KW - metabolism

KW - mitochondrial dynamics

KW - oxidative stress

KW - reactive oxygen species

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