The dynamics of mitochondrial autophagy at the initiation stage

Ktistakis, Nicholas T.

doi:10.1042/bst20210272

Cited by 6 publications

(4 citation statements)

References 83 publications

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“…In PRKN and PINK1 patients with PD, the failure to clear damaged mitochondria via mitophagy is thought to contribute to disease due to the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (2,3). Selective autophagy proceeds from the recognition of cargoes, formation of autophagy initiation sites, de novo synthesis of a double lipid bilayer termed the phagophore (or isolation membrane), maturation of the phagophore into a closed autophagosome that sequesters cargo, and, lastly, autophagosome-lysosome fusion leading to cargo degradation (4)(5)(6). A set of core autophagy initiation proteins bridge cargo recognition to isolation membrane biogenesis and elongation into the cup-shaped phagophore (4,5).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation

et al. 2023

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The assembly of the autophagy initiation machinery nucleates autophagosome biogenesis, including in the PINK1- and Parkin-dependent mitophagy pathway implicated in Parkinson’s disease. The structural interaction between the sole transmembrane autophagy protein, autophagy-related protein 9A (ATG9A), and components of the Unc-51–like autophagy activating kinase (ULK1) complex is one of the major missing links needed to complete a structural map of autophagy initiation. We determined the 2.4-Å x-ray crystallographic structure of the ternary structure of ATG9A carboxyl-terminal tail bound to the ATG13:ATG101 Hop1/Rev7/Mad2 (HORMA) dimer, which is part of the ULK1 complex. We term the interacting portion of the extreme carboxyl-terminal part of the ATG9A tail the “HORMA dimer–interacting region” (HDIR). This structure shows that the HDIR binds to the HORMA domain of ATG101 by β sheet complementation such that the ATG9A tail resides in a deep cleft at the ATG13:ATG101 interface. Disruption of this complex in cells impairs damage-induced PINK1/Parkin mitophagy mediated by the cargo receptor NDP52.

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Section: Introductionmentioning

confidence: 99%

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation

et al. 2023

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“…In PRKN and PINK1 PD patients, the failure to clear damaged mitochondria via mitophagy is thought to contribute to disease due to the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (Panicker et al 2021; Singh and Muqit 2020). Selective autophagy proceeds from the recognition of cargoes, formation of autophagy initiation sites, de novo synthesis of a double lipid bilayer termed the phagophore (or isolation membrane), maturation of the phagophore into a closed autophagosome which sequesters cargo, and finally autophagosome-lysosome fusion leading to cargo degradation (Chang, Jensen, and Hurley 2021; Ktistakis 2021; Maruyama et al 2021). A set of core autophagy initiation proteins bridge cargo recognition to isolation membrane biogenesis and elongation into the cup shaped phagophore (Chang, Jensen, and Hurley 2021; Maruyama et al 2021).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation

Ren

Nguyen

Lam

et al. 2022

Preprint

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The assembly of the autophagy initiation machinery nucleates autophagosome biogenesis, including in the PINK1- and Parkin-dependent mitophagy pathway implicated in Parkinson's disease. The structural interaction between the sole transmembrane autophagy protein, ATG9A, and components of the ULK1 complex is one of the major missing links needed to complete a structural map of autophagy initiation. We determined the 2.2 Angstrom x-ray crystallographic structure of the ternary structure of ATG9A C-terminal tail bound to the ATG13:ATG101 HORMA dimer, which is part of the ULK1 complex. We term the interacting portion of the extreme C-terminal part of the ATG9A tail the HORMA dimer interacting region (HDIR). This structure shows that the HDIR binds to the HORMA domain of ATG101 by beta-sheet complementation such that the ATG9A tail resides in a deep cleft at the ATG13:ATG101 interface. Disruption of this complex in cells impairs damage induced PINK1/Parkin mitophagy mediated by the cargo receptor NDP52.

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“…Mitophagy, which maintains cellular homeostasis by selectively scavenging damaged or dysfunctional mitochondria, is a key link in regulating MQC ( Ktistakis, 2021 ). Due to the special morphology of neurons, mitochondria are mainly distributed in elongated axons and soma, while lysosomes are concentrated in soma.…”

Section: Discussionmentioning

confidence: 99%

Buyang Huanwu Decoction alleviates cerebral ischemic injury through modulating caveolin-1-mediated mitochondrial quality control

Chen

et al. 2023

Front. Pharmacol.

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Introduction: Mitochondrial quality control (MQC) is an important mechanism of neural repair after cerebral ischemia (CI). Recent studies have shown that caveolin-1 (Cav-1) is an important signaling molecule in the process of CI injury, but its mechanism of regulating MQC after CI is still unclear. Buyang Huanwu Decoction (BHD) is a classic traditional Chinese medicine formula that is often used to treat CI. Unfortunately, its mechanism of action is still obscure.Methods: In this study, we tested the hypothesis that BHD can regulate MQC through Cav-1 and exert an anti-cerebral ischemia injury effect. We used Cav-1 knockout mice and their homologous wild-type mice, replicated middle cerebral artery occlusion (MCAO) model and BHD intervention. Neurobehavioral scores and pathological detection were used to evaluate neurological function and neuron damage, transmission electron microscopy and enzymology detection of mitochondrial damage. Finally, western blot and RT-qPCR expression of MQC-related molecules were tested.Results: After CI, mice showed neurologic impairment, neuronal damage, and significant destruction of mitochondrial morphology and function, and MQC was imbalanced. Cav-1 deletion aggravated the damage to neurological function, neurons, mitochondrial morphology and mitochondrial function after CI, aggravated the imbalance of mitochondrial dynamics, and inhibited mitophagy and biosynthesis. BHD can maintain MQC homeostasis after CI through Cav-1 and improve CI injury.Discussion: Cav-1 can affect CI injury by regulating MQC, and this mechanism may be another target of BHD for anti-cerebral ischemia injury.

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The dynamics of mitochondrial autophagy at the initiation stage

Cited by 6 publications

References 83 publications

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation

Buyang Huanwu Decoction alleviates cerebral ischemic injury through modulating caveolin-1-mediated mitochondrial quality control

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