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.
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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Circulation research | 2021 |
Mitochondrial Bioenergetics and Dynamism in the Failing Heart
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Life Sciences | 2021 |
Physical Exercise: A Novel Tool to Protect Mitochondrial Health
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Frontiers in physiology | 2021 |
Mitochondria and Pharmacologic Cardiac Conditioning—At the Heart of Ischemic Injury
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International journal of molecular sciences | 2021 |
Mitophagy in Human Diseases
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International journal of molecular sciences | 2021 |
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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
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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 |
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Cells | 2021 |
Small Rab GTPases in Intracellular Vesicle Trafficking: The Case of Rab3A/Raphillin-3A Complex in the Kidney
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International journal of molecular sciences | 2021 |
Viral Infection Modulates Mitochondrial Function
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International journal of molecular sciences | 2021 |
Estrogen Plays a Crucial Role in Rab9‐Dependent Mitochondrial Autophagy, Delaying Arterial Senescence
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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
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Frontiers in Cell and Developmental Biology | 2021 |
Emerging Role of Mitophagy in the Heart: Therapeutic Potentials to Modulate Mitophagy in Cardiac Diseases
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Oxidative Medicine & Cellular Longevity | 2021 |
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American Journal of Physiology - Regulatory, Integrative and Comparative Physiology | 2021 |
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Frontiers in Cardiovascular Medicine | 2021 |
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Proceedings of the National Academy of Sciences | 2021 |
Ulk1, Not Ulk2, Is Required for Exercise Training-Induced Improvement of Insulin Response in Skeletal Muscle
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Frontiers in physiology | 2021 |
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Cell & Bioscience | 2021 |
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The Journal of biological chemistry | 2021 |
Prompt Graft Cooling Enhances Cardioprotection during Heart Transplantation Procedures through the Regulation of Mitophagy
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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
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Autophagy | 2021 |
Mitophagy Disequilibrium, a Prominent Pathological Mechanism in Metabolic Heart Diseases
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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
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Frontiers in Cardiovascular Medicine | 2021 |
Lats2 promotes heart failure by stimulating p53-mediated apoptosis during pressure overload
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Scientific Reports | 2021 |
Extensive mitochondrial proteome disturbance occurs during the early stages of acute myocardial ischemia
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Experimental and therapeutic medicine | 2021 |
Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis
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Cells | 2021 |
The role of autophagy in cardiovascular pathology
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Cardiovascular Research | 2021 |
Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling
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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
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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
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Cardiovascular Research | 2020 |
Targeting mitochondrial fusion and fission proteins for cardioprotection
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Journal of Cellular and Molecular Medicine | 2020 |
The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction
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Cells | 2020 |
O-GlcNAcylation Is Essential for Autophagy in Cardiomyocytes
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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 |