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

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

doi:10.1172/jci122035

Cited by 206 publications

(222 citation statements)

References 40 publications

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“…Even though mitophagy generally is reported to occur via the canonical autophagic machinery that we described earlier, a non-canonical mitophagy pathway which does not require LC3 lipidation was reported to occur in cardiomyocytes upon ischemic stress and starvation as well as in HeLa cells upon starvation and hypoxia (Hirota et al, 2015;Saito et al, 2019). In cardiomyocytes, this pathway depends on ULK1 but not on ATG5 and does not involve LC3-positive autophagosomes; instead it is mediated by Rab9 positive membranes/vesicles which drive lysosomal degradation of mitochondria.…”

Section: Recruitment Of the Autophagic Machinerymentioning

confidence: 85%

“…More specifically, acute exercise is a strong mitophagy inducer in heart and skeletal muscle to mediate mitochondrial remodeling (Moyzis et al, 2015;Laker et al, 2017;Drake et al, 2019). Starvation is well known to induce general autophagy in mice, but this stress has also been reported to induce mitophagy, and interestingly there is evidence for canonical and non-canonical mechanisms occurring during starvation-induced mitophagy (discussed below) (Mizushima et al, 2004;Nishida et al, 2009;Hirota et al, 2015;Saito et al, 2019). Cardiomyocytes from mice subjected to high fat diet were shown to exhibit elevated levels of mitophagy to prevent cytotoxicity (Tong et al, 2019), although this resulted in reduced mitophagy in liver (Sun et al, 2015).…”

Section: Induction Of Mitophagy In Vivomentioning

confidence: 99%

“…Cardiomyocytes from mice subjected to high fat diet were shown to exhibit elevated levels of mitophagy to prevent cytotoxicity (Tong et al, 2019), although this resulted in reduced mitophagy in liver (Sun et al, 2015). Myocardial ischemia and energy stress (48 h starvation) have been shown to induce mitophagy in cardiomyocytes of mice, whereas ischemic preconditioning as well as ischemiareperfusion injury were shown to induce mitophagy in kidney and brain tissues Livingston et al, 2019;Saito et al, 2019;Tang et al, 2019). Hypoxic conditions also result in mitophagy induction in multiple tissues in mice and in various cell lines in vitro Allen et al, 2013;Sun et al, 2015, Zhang W. et al, 2016.…”

Section: Induction Of Mitophagy In Vivomentioning

confidence: 99%

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Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

Zachari

Ktistakis

2020

Front. Cell Dev. Biol.

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Mitophagy, a conserved intracellular process by which mitochondria are eliminated via the autophagic machinery, is a quality control mechanism which facilitates maintenance of a functional mitochondrial network and cell homeostasis, making it a key process in development and longevity. Mitophagy has been linked to multiple human disorders, especially neurodegenerative diseases where the long-lived neurons are relying on clearance of old/damaged mitochondria to survive. During the past decade, the availability of novel tools to study mitophagy both in vitro and in vivo has significantly advanced our understanding of the molecular mechanisms governing this fundamental process in normal physiology and in various disease models. We here give an overview of the known mitophagy pathways and how they are induced, with a particular emphasis on the early events governing mitophagosome formation.

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Section: Recruitment Of the Autophagic Machinerymentioning

confidence: 85%

Section: Induction Of Mitophagy In Vivomentioning

confidence: 99%

Section: Induction Of Mitophagy In Vivomentioning

confidence: 99%

See 1 more Smart Citation

Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

Zachari

Ktistakis

2020

Front. Cell Dev. Biol.

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“…However, the mechanisms responsible for MDV formation in the early phases of hypoxia and MDV degradation following prolonged exposure to hypoxic conditions remain to be explored. Rab9 appears to be the prime candidate for the mediation of this effect, as it plays a critical role in MDV production (Matheoud et al, 2016) and myocardial ischemia (Saito et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial-Derived Vesicles Protect Cardiomyocytes Against Hypoxic Damage

Zhao

et al. 2020

Front. Cell Dev. Biol.

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Myocardial ischemia is a condition with insufficient oxygen supporting the heart tissues, which may result from myocardial infarction or trauma-induced hemorrhagic shock. In order to develop better preventive and therapeutic strategies for myocardial ischemic damage, it is important that we understand the mechanisms underlying this type of injury. Mitochondrial-derived vesicles (MDVs) have been proposed as a novel player in maintaining mitochondrial quality control. This study aimed to investigate the role and possible mechanisms of MDVs in ischemia/hypoxia-induced myocardial apoptosis. H9C2 cardiomyocytes were used for the cellular experiments. A 40% fixed blood volume hemorrhagic shock rat model was used to construct the acute general ischemic models. MDVs were detected using immunofluorescence staining with PDH and TOM20. Exogenous MDVs were reconstituted in vitro from isolated mitochondria under different hypoxic conditions. The results demonstrate that MDV production was negatively correlated with cardiomyocyte apoptosis under hypoxic conditions; exogenous MDVs inhibited hypoxia-induced cardiomyocyte apoptosis; and MDV-mediated protection against hypoxia-induced cardiomyocyte apoptosis was accomplished via Bcl-2 interactions in the mitochondrial pathway. This study provides evidence that MDVs protect cardiomyocytes against hypoxic damage by inhibiting mitochondrial apoptosis. Our study used a novel approach that expands our understanding of MDVs and highlights that MDVs may be part of the endogenous response to hypoxia designed to mitigate damage. Strategies that stimulate cardiomyocytes to produce cargo-specific MDVs, including Bcl-2 containing MDVs, could theoretically be helpful in treating ischemic/hypoxic myocardial injury.

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“…This process impairs the reuse of dysfunctional mitochondria and subsequently induces the development of cardiac dysfunction [67] (Table 1). Recent studies on KO mouse models have also highlighted a role for Ulk1-dependent mitophagy in the protection of the heart against pressure overload-induced HF [146].…”

Section: Heart Failurementioning

confidence: 99%

Mitophagy in Cardiovascular Diseases

Morciano

Patergnani

Bonora

et al. 2020

JCM

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Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes.

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

Cited by 206 publications

References 40 publications

Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

Mitochondrial-Derived Vesicles Protect Cardiomyocytes Against Hypoxic Damage

Mitophagy in Cardiovascular Diseases

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