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Citations to this article

An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia
Toshiro Saito, … , Mondira Kundu, Junichi Sadoshima
Toshiro Saito, … , Mondira Kundu, Junichi Sadoshima
Published December 4, 2018
Citation Information: J Clin Invest. 2019;129(2):802-819. https://doi.org/10.1172/JCI122035.
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Research Article Cardiology Cell biology Article has an altmetric score of 4

An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia

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Abstract

Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of trans-Golgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.

Authors

Toshiro Saito, Jihoon Nah, Shin-ichi Oka, Risa Mukai, Yoshiya Monden, Yasuhiro Maejima, Yoshiyuki Ikeda, Sebastiano Sciarretta, Tong Liu, Hong Li, Erdene Baljinnyam, Diego Fraidenraich, Luke Fritzky, Peiyong Zhai, Shizuko Ichinose, Mitsuaki Isobe, Chiao-Po Hsu, Mondira Kundu, Junichi Sadoshima

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Autophagy 2021
Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis
O Mareninova, D Dillon, C Wightman, I Yakubov, T Takahashi, H Gaisano, K Munson, M Ohmuraya, D Dawson, I Gukovsky, A Gukovskaya
CMGH Cellular and Molecular Gastroenterology and Hepatology 2021
Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury
M Xie, GW Cho, Y Kong, DL Li, F Altamirano, X Luo, CR Morales, N Jiang, GG Schiattarella, HI May, J Medina, JM Shelton, A Ferdous, TG Gillette, JA Hill
Circulation research 2021
Mitochondrial Bioenergetics and Dynamism in the Failing Heart
G Morciano, VA Vitto, E Bouhamida, C Giorgi, P Pinton
Life Sciences 2021
Physical Exercise: A Novel Tool to Protect Mitochondrial Health
D Sorriento, ED Vaia, G Iaccarino
Frontiers in physiology 2021
Mitochondria and Pharmacologic Cardiac Conditioning—At the Heart of Ischemic Injury
C Lotz, J Herrmann, Q Notz, P Meybohm, F Kehl
International journal of molecular sciences 2021
Mitophagy in Human Diseases
L Doblado, C Lueck, C Rey, AK Samhan-Arias, I Prieto, A Stacchiotti, M Monsalve
International journal of molecular sciences 2021
At the heart of mitochondrial quality control: many roads to the top
RA Gottlieb, H Piplani, J Sin, S Sawaged, SM Hamid, DJ Taylor, J de Freitas Germano
Cellular and Molecular Life Sciences 2021
Managing risky assets – mitophagy in vivo
DP Narendra
Journal of cell science 2021
Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms
H Zheng, H Zhu, X Liu, X Huang, A Huang, Y Huang
Frontiers in Cell and Developmental Biology 2021
The role of mitophagy during oocyte aging in human, mouse, and Drosophila: implications for oocyte quality and mitochondrial disease
R Cox, J Poulton, S Williams
2021
Molecular Signaling to Preserve Mitochondrial Integrity against Ischemic Stress in the Heart: Rescue or Remove Mitochondria in Danger
JD Yu, S Miyamoto
Cells 2021
Small Rab GTPases in Intracellular Vesicle Trafficking: The Case of Rab3A/Raphillin-3A Complex in the Kidney
O Martinez-Arroyo, E Selma-Soriano, A Ortega, R Cortes, J Redon
International journal of molecular sciences 2021
Viral Infection Modulates Mitochondrial Function
X Li, K Wu, S Zeng, F Zhao, J Fan, Z Li, L Yi, H Ding, M Zhao, S Fan, J Chen
International journal of molecular sciences 2021
Estrogen Plays a Crucial Role in Rab9‐Dependent Mitochondrial Autophagy, Delaying Arterial Senescence
Y Sasaki, Y Ikeda, Y Uchikado, Y Akasaki, J Sadoshima, M Ohishi
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease 2021
Ubiquitination-Dependent Regulation of Small GTPases in Membrane Trafficking: From Cell Biology to Human Diseases
Z Lei, J Wang, L Zhang, CH Liu
Frontiers in Cell and Developmental Biology 2021
Emerging Role of Mitophagy in the Heart: Therapeutic Potentials to Modulate Mitophagy in Cardiac Diseases
Y Luan, Y Luan, Q Feng, X Chen, KD Ren, Y Yang, S Toan
Oxidative Medicine & Cellular Longevity 2021
Proteomic analysis of mitochondrial biogenesis in cardiomyocytes differentiated from human induced pluripotent stem cells
S Venkatesh, E Baljinnyam, M Tong, T Kashihara, L Yan, T Liu, H Li, LH Xie, M Nakamura, S Oka, CK Suzuki, D Fraidenraich, J Sadoshima
American Journal of Physiology - Regulatory, Integrative and Comparative Physiology 2021
Advances in Cardiotoxicity Induced by Altered Mitochondrial Dynamics and Mitophagy
Y Yin, H Shen
Frontiers in Cardiovascular Medicine 2021
Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy
JC Drake, RJ Wilson, RC Laker, Y Guan, HR Spaulding, AS Nichenko, W Shen, H Shang, MV Dorn, K Huang, M Zhang, AB Bandara, MH Brisendine, JA Kashatus, PR Sharma, A Young, J Gautam, R Cao, H Wallrabe, PA Chang, M Wong, EM Desjardins, SA Hawley, GJ Christ, DF Kashatus, CL Miller, MJ Wolf, A Periasamy, GR Steinberg, DG Hardie, Z Yan
Proceedings of the National Academy of Sciences 2021
Ulk1, Not Ulk2, Is Required for Exercise Training-Induced Improvement of Insulin Response in Skeletal Muscle
JC Drake, RJ Wilson, D Cui, Y Guan, M Kundu, M Zhang, Z Yan
Frontiers in physiology 2021
Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases
X Chen, J Wang, M Tahir, F Zhang, Y Ran, Z Liu, J Wang
Cell & Bioscience 2021
Regulation of mitochondrial cargo-selective autophagy by post-translational modifications
AL Terradas, K Zittlau, B Macek, M Fraiberg, Z Elazar, PJ Kahle
The Journal of biological chemistry 2021
Prompt Graft Cooling Enhances Cardioprotection during Heart Transplantation Procedures through the Regulation of Mitophagy
Z Wu, J Liang, W Huang, L Jiang, C Paul, B Lin, J Zheng, Y Wang
Cells 2021
Endosomal Rab GTPases regulate secretory granule maturation in Drosophila larval salivary glands
CI Ma, JA Brill
Communicative & integrative biology 2021
Mitochondrial autophagy and cell survival is regulated by the circadian Clock gene in cardiac myocytes during ischemic stress
I Rabinovich-Nikitin, M Rasouli, CJ Reitz, I Posen, V Margulets, R Dhingra, TN Khatua, JA Thliveris, TA Martino, LA Kirshenbaum
Autophagy 2021
Mitophagy Disequilibrium, a Prominent Pathological Mechanism in Metabolic Heart Diseases
Y Li, N Zheng, X Ding
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021
The Secrets of Alternative Autophagy
K Urbańska, A Orzechowski
Cells 2021
Association of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 With Angiotensin II Type 1 Receptor Impacts Mitochondrial Quality Control, Offering Promise for the Treatment of Vascular Senescence
Y Uchikado, Y Ikeda, Y Sasaki, M Iwabayashi, Y Akasaki, M Ohishi
Frontiers in Cardiovascular Medicine 2021
Lats2 promotes heart failure by stimulating p53-mediated apoptosis during pressure overload
D Shao, P Zhai, C Hu, R Mukai, S Sciarretta, DD Re, J Sadoshima
Scientific Reports 2021
Extensive mitochondrial proteome disturbance occurs during the early stages of acute myocardial ischemia
J Wang, J He, Y Fan, F Xu, Q Liu, R He, R Yan
Experimental and therapeutic medicine 2021
Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis
R Iorio, G Celenza, S Petricca
Cells 2021
The role of autophagy in cardiovascular pathology
D Gatica, M Chiong, S Lavandero, D Klionsky
Cardiovascular Research 2021
Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling
S Ljubojević-Holzer, S Kraler, N Djalinac, M Abdellatif, J Voglhuber, J Schipke, M Schmidt, K Kling, G Franke, V Herbst, A Zirlik, D von Lewinski, D Scherr, P Rainer, M Kohlhaas, A Nickel, C Mühlfeld, C Maack, S Sedej
Cardiovascular Research 2021
Mitochondrial Quality Control and Cellular Proteostasis: Two Sides of the Same Coin
JM Quiles, ÅB Gustafsson
Frontiers in physiology 2020
Mitochondrial ROS Formation in the Pathogenesis of Diabetic Cardiomyopathy
N Kaludercic, FD Lisa
Frontiers in Cardiovascular Medicine 2020
Autophagy involvement in oncogenesis
S Torii, S Honda, M Murohashi, H Yamaguchi, S Shimizu
Cancer Science 2020
Mitophagy in Cardiovascular Diseases
G Morciano, S Patergnani, M Bonora, G Pedriali, A Tarocco, E Bouhamida, S Marchi, G Ancora, G Anania, MR Wieckowski, C Giorgi, P Pinton
Journal of Clinical Medicine 2020
Molecular Mechanisms And Clinical Implications Of Multiple Forms Of Mitophagy In The Heart
T Saito, K Hamano, J Sadoshima
Cardiovascular Research 2020
Targeting mitochondrial fusion and fission proteins for cardioprotection
S HernandezResendiz, F Prunier, H Girao, G Dorn, DJ Hausenloy
Journal of Cellular and Molecular Medicine 2020
The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction
A Bellis, C Mauro, E Barbato, GD Gioia, D Sorriento, B Trimarco, C Morisco
Cells 2020
O-GlcNAcylation Is Essential for Autophagy in Cardiomyocytes
H Yu, L Wen, Y Mu
Oxidative medicine and cellular longevity 2020
Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission
J Wang, P Zhu, R Li, J Ren, H Zhou
Redox Biology 2020
Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps
M Zachari, NT Ktistakis
Frontiers in Cell and Developmental Biology 2020
Mitochondrial-Derived Vesicles Protect Cardiomyocytes Against Hypoxic Damage
B Li, H Zhao, Y Wu, Y Zhu, J Zhang, G Yang, Q Yan, J Li, T Li, L Liu
Frontiers in Cell and Developmental Biology 2020
Mitophagy in cardiovascular homeostasis
R Zhang, J Krigman, H Luo, S Ozgen, M Yang, N Sun
Mechanisms of Ageing and Development 2020
Impaired mitochondrial–endoplasmic reticulum interaction and mitophagy in Miro1-mutant neurons in Parkinson’s disease
C Berenguer-Escuder, D Grossmann, P Antony, G Arena, K Wasner, F Massart, J Jarazo, J Walter, JC Schwamborn, A Grünewald, R Krüger
Human Molecular Genetics 2020
DNA damage invokes mitophagy through a pathway involving Spata18
X Dan, M Babbar, A Moore, N Wechter, J Tian, JG Mohanty, DL Croteau, VA Bohr
Nucleic Acids Research 2020
Mitophagy pathways in health and disease
SA Killackey, DJ Philpott, SE Girardin
The Journal of Cell Biology 2020
Mitochondria in acute myocardial infarction and cardioprotection
CJ Ramachandra, S Hernandez-Resendiz, GE Crespo-Avilan, YH Lin, DJ Hausenloy
EBioMedicine 2020
A Healthy Heart and a Healthy Brain: Looking at Mitophagy
H Luo, R Zhang, J Krigman, A McAdams, S Ozgen, N Sun
Frontiers in Cell and Developmental Biology 2020
Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling
W Li, L Yin, X Sun, J Wu, Z Dong, K Hu, A Sun, J Ge
Cell Death and Disease 2020
Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration
H Yamaguchi, S Honda, S Torii, K Shimizu, K Katoh, K Miyake, N Miyake, N Fujikake, HT Sakurai, S Arakawa, S Shimizu
Nature Communications 2020
Mitochondrial Dynamics Imbalance: A Strategy for Promoting Viral Infection
Z Ren, X Zhang, T Ding, Z Zhong, H Hu, Z Xu, J Deng
Frontiers in microbiology 2020
The role of Drp1 in mitophagy and cell death in the heart
M Tong, D Zablocki, J Sadoshima
Journal of Molecular and Cellular Cardiology 2020
Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia–reperfusion injury
J Wang, H Zhou
Acta pharmaceutica Sinica. B 2020
Phosphorylation of Rab GTPases in the regulation of membrane trafficking
D Waschbüsch, AR Khan
Traffic (Copenhagen, Denmark) 2020
HIF1α or mitophagy: which drives cardiomyocyte differentiation?
B Villarejo-Zori, JI Jiménez-Loygorri, P Boya
2020
Ulk1/Rab9-mediated alternative mitophagy confers cardioprotection during energy stress
Rimpy Dhingra, Inna Rabinovich-Nikitin, Lorrie Kirshenbaum
Journal of Clinical Investigation 2019
Posttranslational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology
SM Adaniya, J O-Uchi, MW Cypress, Y Kusakari, BS Jhun
American journal of physiology. Cell physiology 2019
Comprehensive autophagy evaluation in cardiac disease models
N Kaludercic, MC Maiuri, S Kaushik, ÁF Fernández, J de Bruijn, F Castoldi, Y Chen, J Ito, R Mukai, T Murakawa, J Nah, F Pietrocola, T Saito, S Sebti, M Semenzato, L Tsansizi, S Sciarretta, J Madrigal-Matute
Cardiovascular Research 2019
Mitofusins: Disease Gatekeepers and Hubs in Mitochondrial Quality Control by E3 Ligases
M Escobar-Henriques, M Joaquim
Frontiers in physiology 2019
The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia
C Lechauve, J Keith, E Khandros, S Fowler, K Mayberry, A Freiwan, CS Thom, P Delbini, EB Romero, J Zhang, I Motta, H Tillman, MD Cappellini, M Kundu, MJ Weiss
Science Translational Medicine 2019
Role of YAP/TAZ in Energy Metabolism in the Heart:
T Kashihara, J Sadoshima
Journal of Cardiovascular Pharmacology 2019
MicroRNA Let-7d-3p Contributes to Cardiac Protection via Targeting HMGA2
L Wong, E Saw, J Lim, Y Zhou, A Richards, P Wang
International journal of molecular sciences 2019
Methods to detect mitophagy in neurons during disease
FE Carter, ME Moore, AM Pickrell
Journal of Neuroscience Methods 2019
Melatonin has profound effects on mitochondrial dynamics in myocardial ischaemia/reperfusion
K Dube, K Dhanabalan, R Salie, M Blignaut, B Huisamen, A Lochner
Heliyon 2019
Intrafibrillar and perinuclear mitochondrial heterogeneity in adult cardiac myocytes
X Lu, PN Thai, S Lu, J Pu, DM Bers
Journal of Molecular and Cellular Cardiology 2019
Precision remodeling: how exercise improves mitochondrial quality in myofibers
JC Drake, Z Yan
Current Opinion in Physiology 2019
The impact of endothelial cell death in the brain and its role after stroke: A systematic review
M Zille, M Ikhsan, Y Jiang, J Lampe, J Wenzel, M Schwaninger
2019
Mitochondrial oxidative phosphorylation and mitophagy in myocardial ischaemia/reperfusion: effects of chloroquine.
Dhanabalan K, Huisamen B, Lochner A
CardioVascular Journal of Africa 2019
Adrenergic Regulation of Drp1-Driven Mitochondrial Fission in Cardiac Physio-Pathology
B Jhun, J O-Uchi, S Adaniya, M Cypress, Y Yoon
Antioxidants 2018

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