FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury

Ji, Haizhe; Wang, Jin; Muid, David; Song, Wei; Zhou, Hao

doi:10.1016/j.cellsig.2022.110249

Cited by 18 publications

(8 citation statements)

References 76 publications

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“…In a mouse model of myocardial ischemia/reperfusion, UPRmt activation, and inhibition alleviate and aggravate ischemia/reperfusion-mediated damage, respectively, even under slight activation of the UPRmt. Notably, the knockout of FUNDC1 in this model downregulates the expression of UPRmt-related mtDNA genes, such as CLpP, LONP1, and HSP10, whereas FUNDC1-transgenic mice show upregulated expression of these genes, indicating that FUNDC1 mediates the coordination of the UPRmt and mitophagy and may act upstream of the UPRmt pathway [51]. Moreover, ATF5 knockout-induced UPRmt depression reverses the cardioprotection induced by UPRmt activation, which leads to myocardial infarction area expansion and myocardial dysfunction [52].…”

Section: Fundc1mentioning

confidence: 85%

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Wang

Zhang

et al. 2023

Life

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The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.

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Section: Fundc1mentioning

confidence: 85%

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Wang

Zhang

et al. 2023

Life

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“…When this stress response is activated, GrpEL1 forms a complex with mtHsp70 to promote its function and reduce the aggregation of proteins in mitochondria (Ma et al, 2022). Additionally, a recent study suggested that the UPR mt is linked to and dependent on mitophagy, with FUN14 domain-containing protein 1 (FUNDC1) acting upstream of its activation, inducing this stress response by decreasing the mtDNA content (Ji et al, 2022), which increases the misfolded protein load. Moreover, recently, it was shown that the activation of the UPR mt , in addition to the release of short DELE1 fragments, requires the release of mitochondrial ROS (mtROS) as signaling molecules into the cytosol (Sutandy et al, 2023).…”

Section: Upr Mt Regulationmentioning

confidence: 99%

Mitochondrial unfolded protein response (UPRmt): what we know thus far

Torres,

Fleischhart,

Inestrosa

2024

Front. Cell Dev. Biol.

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Mitochondria are key organelles for the optimal function of the cell. Among their many functions, they maintain protein homeostasis through their own proteostatic machinery, which involves proteases and chaperones that regulate protein import and folding inside mitochondria. In the early 2000s, the mitochondrial unfolded protein response (UPRmt) was first described in mammalian cells. This stress response is activated by the accumulation of unfolded/misfolded proteins within the mitochondrial matrix, which results in the transmission of a signal to the nucleus to increase the expression of proteases and chaperones to address the abnormal mitochondrial protein load. After its discovery, this retrograde signaling pathway has also been described in other organisms of different complexities, suggesting that it is a conserved stress response. Although there are some specific differences among organisms, the mechanism of this stress response is mostly similar and involves the transmission of a signal from mitochondria to the nucleus that induces chromatin remodeling to allow the binding of specific transcription factors to the promoters of chaperones and proteases. In the last decade, proteins and signaling pathways that could be involved in the regulation of the UPRmt, including the Wnt signaling pathway, have been described. This minireview aims to summarize what is known about the mechanism of the UPRmt and its regulation, specifically in mammals and C. elegans.

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“…The mitochondrial unfolded protein response involves in the activation of proteases, chaperones, and antioxidant enzymes and is used to degrade abnormal or unfolded proteins and restore mitochondrial function. FUNDC1 activates the mitochondrial unfolded protein response to inhibit mitochondrial oxidative stress and stimulate mitochondrial biogenesis under myocardial I/R injury [ 56 ]. In addition, OPA1 is predominately embedded in the mitochondrial membrane, intimately linked to the degradation of damaged mitochondria through mitophagy [ 57 ].…”

Section: Mitochondrial Damage In Ischemia/reperfusion Injurymentioning

confidence: 99%

Mitochondrial Damage in Myocardial Ischemia/Reperfusion Injury and Application of Natural Plant Products

Zhou

et al. 2022

Oxidative Medicine and Cellular Longevity

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Ischemic heart disease (IHD) is currently one of the leading causes of death among cardiovascular diseases worldwide. In addition, blood reflow and reperfusion paradoxically also lead to further death of cardiomyocytes and increase the infarct size. Multiple evidences indicated that mitochondrial function and structural disorders were the basic driving force of IHD. We summed up the latest evidence of the basic associations and underlying mechanisms of mitochondrial damage in the event of ischemia/reperfusion (I/R) injury. This review then reviewed natural plant products (NPPs) which have been demonstrated to mitochondria-targeted therapeutic effects during I/R injury and the potential pathways involved. We realized that NPPs mainly maintained the integrality of mitochondria membrane and ameliorated dysfunction, such as improving abnormal mitochondrial calcium handling and inhibiting oxidative stress, so as to protect cardiomyocytes during I/R injury. This information will improve our knowledge of mitochondrial biology and I/R-induced injury’s pathogenesis and exhibit that NPPs hold promise for translation into potential therapies that target mitochondria.

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FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury

Cited by 18 publications

References 76 publications

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Mitochondrial unfolded protein response (UPRmt): what we know thus far

Mitochondrial Damage in Myocardial Ischemia/Reperfusion Injury and Application of Natural Plant Products

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