The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
Hao Zhou - One of the best experts on this subject based on the ideXlab platform.
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FUNDC1 interacts with fbxl2 to govern mitochondrial integrity and cardiac function through an ip3r3 dependent manner in obesity
Science Advances, 2020Co-Authors: Jun Ren, Hao Zhou, Mingming Sun, Amir Ajoolabady, Yuan Zhou, Jun TaoAbstract:Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca2+ homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1-/- mice accentuated high-fat diet-induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca2+ overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid-induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca2+ homeostasis and cardiac function in obese hearts.
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FUNDC1 dependent mitophagy is obligatory to ischemic preconditioning conferred renoprotection in ischemic aki via suppression of drp1 mediated mitochondrial fission
Redox biology, 2020Co-Authors: Jin Wang, Jun Ren, Hao Zhou, Pingjun ZhuAbstract:FUN14 domain-containing protein 1 (FUNDC1)-dependent mitophagy, mainly activated by ischemic/hypoxic preconditioning, benefits acute myocardial reperfusion injury and chronic metabolic syndrome via sustaining mitochondrial homeostasis. Mitochondrial fission plays a pathogenic role in ischemic acute kidney injury (AKI) through perturbation of mitochondrial quality and activation of mitochondrial apoptosis. The aim of our study was to explore the role of FUNDC1 mitophagy in ischemia preconditioning (IPC)-mediated renoprotection. Proximal tubule-specific FUNDC1 knockout (FUNDC1PTKO) mice were subjected to ischemia reperfusion injury (IRI) and IPC prior to assessment of renal function, mitophagy, mitochondrial quality control, and Drp1-related mitochondrial fission. Following exposure to IPC, FUNDC1 mitophagy was activated through post-transcriptional phosphorylation at Ser17. Interestingly, IRI-mediated renal injury, inflammation, and tubule cell death were mitigated by IPC whereas proximal tubule-specific FUNDC1 knockout (FUNDC1PTKO) mice abolished IPC-offered renoprotection. Mechanistically, IRI-evoked mitochondrial damage was improved by IPC whereas FUNDC1 deficiency provoked mitochondrial abnormality, manifested by impaired mitochondrial quality and hyperactivated Drp1-dependent mitochondrial fission. Interestingly, FUNDC1 deficiency-associated mitochondrial dysfunction was reversed by pharmacological inhibition of mitochondrial fission. In vivo, FUNDC1 deletion-caused renal injury, severe pro-inflammatory response, and tubule cell death could be nullified by way of knockout Drp1 on FUNDC1PTKO background. Finally, we also revealed that IPC triggered FUNDC1 mitophagy activation through UNC-51-like kinase 1 (Ulk1) and Ulk1 ablation interrupted IPC-mediated FUNDC1 activation and thus attenuated IPC-induced renoprotection. FUNDC1 mitophagy, primarily driven by IPC, confers resistance to AKI through reconciliation of mitochondrial fission, implicating the therapeutic potential of targeting mitochondrial homeostasis for AKI.
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dna pkcs promotes alcohol related liver disease by activating drp1 related mitochondrial fission and repressing FUNDC1 required mitophagy
Signal Transduction and Targeted Therapy, 2019Co-Authors: Hao Zhou, Jin Wang, Sam Toan, Pingjun Zhu, Jun RenAbstract:DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel housekeeper of hepatic mitochondrial homeostasis outside the DNA repair process. In this study, DNA-PKcs was upregulated in the livers of mice that were exposed to alcohol; the expression of DNA-PKcs positively correlated with hepatic steatosis, fibrosis, apoptosis, and mitochondrial damage. Functional studies revealed that liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice were protected from chronic ethanol-induced liver injury and mitochondrial damage. Mechanistic investigations established that DNA-PKcs promoted p53 activation, which elevated dynamin-related protein 1 (Drp1)-related mitochondrial fission but repressed FUN14 domain containing 1 (FUNDC1)-required mitophagy. Excessive fission and defective mitophagy triggered mtDNA damage, mitochondrial respiratory inhibition, mROS overproduction, cardiolipin oxidation, redox imbalance, calcium overload, and hepatic mitochondrial apoptosis. In contrast, the deletion of DNA-PKcs rescued these phenotypic alterations, which alleviated the susceptibility of hepatocytes to alcohol-induced cytotoxicity. Additionally, we also showed that orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) was the upstream signal for DNA-PKcs activation and that the genetic ablation of NR4A1 ameliorated the progression of alcohol-related liver disease (ARLD); these results were similar to those obtained in DNA-PKcs knockout mice. Collectively, our results identified the NR4A1/DNA-PKcs/p53 axis as a novel signaling pathway responsible for ARLD pathogenesis that acts by activating Drp1-related mitochondrial fission and restricting FUNDC1-required mitophagy. The findings have potential implications for new approaches for ARLD therapy.
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nr4a1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1 mediated mitophagy and promoting mff required mitochondrial fission by ck2α
Basic Research in Cardiology, 2018Co-Authors: Hao Zhou, Shunying Hu, Jin Wang, Sam Toan, Yundai ChenAbstract:Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.
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pathogenesis of cardiac ischemia reperfusion injury is associated with ck2α disturbed mitochondrial homeostasis via suppression of FUNDC1 related mitophagy
Cell Death & Differentiation, 2018Co-Authors: Jun Ren, Hao Zhou, Jin Wang, Pingjun Zhu, Hong Zhu, Yundai ChenAbstract:Disturbed mitochondrial homeostasis contributes to the pathogenesis of cardiac ischemia reperfusion (IR) injury, although the underlying mechanism remains elusive. Here, we demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury. Increased CK2α was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2α knockout (CK2α CKO ) mice were protected against IR injury and mitochondrial damage. Functional assay indicated that CK2α enhanced the phosphorylation (inactivation) of FUN14 domain containing 1 (FUNDC1) via post-transcriptional modification at Ser13, thus effectively inhibiting mitophagy. Defective mitophagy failed to remove damaged mitochondria induced by IR injury, resulting in mitochondrial genome collapse, electron transport chain complex (ETC) inhibition, mitochondrial biogenesis arrest, cardiolipin oxidation, oxidative stress, mPTP opening, mitochondrial debris accumulation and eventually mitochondrial apoptosis. In contrast, loss of CK2α reversed the FUNDC1-mediated mitophagy, providing a survival advantage to myocardial tissue following IR stress. Interestingly, mice deficient in both CK2α and FUNDC1 failed to show protection against IR injury and mitochondrial damage through a mechanism possible attributed to lack of mitophagy. Taken together, our results confirmed that CK2α serves as a negative regulator of mitochondrial homeostasis via suppression of FUNDC1-required mitophagy, favoring the development of cardiac IR injury.
Jun Ren - One of the best experts on this subject based on the ideXlab platform.
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FUNDC1 interacts with fbxl2 to govern mitochondrial integrity and cardiac function through an ip3r3 dependent manner in obesity
Science Advances, 2020Co-Authors: Jun Ren, Hao Zhou, Mingming Sun, Amir Ajoolabady, Yuan Zhou, Jun TaoAbstract:Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca2+ homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1-/- mice accentuated high-fat diet-induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca2+ overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid-induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca2+ homeostasis and cardiac function in obese hearts.
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FUNDC1 dependent mitophagy is obligatory to ischemic preconditioning conferred renoprotection in ischemic aki via suppression of drp1 mediated mitochondrial fission
Redox biology, 2020Co-Authors: Jin Wang, Jun Ren, Hao Zhou, Pingjun ZhuAbstract:FUN14 domain-containing protein 1 (FUNDC1)-dependent mitophagy, mainly activated by ischemic/hypoxic preconditioning, benefits acute myocardial reperfusion injury and chronic metabolic syndrome via sustaining mitochondrial homeostasis. Mitochondrial fission plays a pathogenic role in ischemic acute kidney injury (AKI) through perturbation of mitochondrial quality and activation of mitochondrial apoptosis. The aim of our study was to explore the role of FUNDC1 mitophagy in ischemia preconditioning (IPC)-mediated renoprotection. Proximal tubule-specific FUNDC1 knockout (FUNDC1PTKO) mice were subjected to ischemia reperfusion injury (IRI) and IPC prior to assessment of renal function, mitophagy, mitochondrial quality control, and Drp1-related mitochondrial fission. Following exposure to IPC, FUNDC1 mitophagy was activated through post-transcriptional phosphorylation at Ser17. Interestingly, IRI-mediated renal injury, inflammation, and tubule cell death were mitigated by IPC whereas proximal tubule-specific FUNDC1 knockout (FUNDC1PTKO) mice abolished IPC-offered renoprotection. Mechanistically, IRI-evoked mitochondrial damage was improved by IPC whereas FUNDC1 deficiency provoked mitochondrial abnormality, manifested by impaired mitochondrial quality and hyperactivated Drp1-dependent mitochondrial fission. Interestingly, FUNDC1 deficiency-associated mitochondrial dysfunction was reversed by pharmacological inhibition of mitochondrial fission. In vivo, FUNDC1 deletion-caused renal injury, severe pro-inflammatory response, and tubule cell death could be nullified by way of knockout Drp1 on FUNDC1PTKO background. Finally, we also revealed that IPC triggered FUNDC1 mitophagy activation through UNC-51-like kinase 1 (Ulk1) and Ulk1 ablation interrupted IPC-mediated FUNDC1 activation and thus attenuated IPC-induced renoprotection. FUNDC1 mitophagy, primarily driven by IPC, confers resistance to AKI through reconciliation of mitochondrial fission, implicating the therapeutic potential of targeting mitochondrial homeostasis for AKI.
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dna pkcs promotes alcohol related liver disease by activating drp1 related mitochondrial fission and repressing FUNDC1 required mitophagy
Signal Transduction and Targeted Therapy, 2019Co-Authors: Hao Zhou, Jin Wang, Sam Toan, Pingjun Zhu, Jun RenAbstract:DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel housekeeper of hepatic mitochondrial homeostasis outside the DNA repair process. In this study, DNA-PKcs was upregulated in the livers of mice that were exposed to alcohol; the expression of DNA-PKcs positively correlated with hepatic steatosis, fibrosis, apoptosis, and mitochondrial damage. Functional studies revealed that liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice were protected from chronic ethanol-induced liver injury and mitochondrial damage. Mechanistic investigations established that DNA-PKcs promoted p53 activation, which elevated dynamin-related protein 1 (Drp1)-related mitochondrial fission but repressed FUN14 domain containing 1 (FUNDC1)-required mitophagy. Excessive fission and defective mitophagy triggered mtDNA damage, mitochondrial respiratory inhibition, mROS overproduction, cardiolipin oxidation, redox imbalance, calcium overload, and hepatic mitochondrial apoptosis. In contrast, the deletion of DNA-PKcs rescued these phenotypic alterations, which alleviated the susceptibility of hepatocytes to alcohol-induced cytotoxicity. Additionally, we also showed that orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) was the upstream signal for DNA-PKcs activation and that the genetic ablation of NR4A1 ameliorated the progression of alcohol-related liver disease (ARLD); these results were similar to those obtained in DNA-PKcs knockout mice. Collectively, our results identified the NR4A1/DNA-PKcs/p53 axis as a novel signaling pathway responsible for ARLD pathogenesis that acts by activating Drp1-related mitochondrial fission and restricting FUNDC1-required mitophagy. The findings have potential implications for new approaches for ARLD therapy.
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double knockout of akt2 and ampk predisposes cardiac aging without affecting lifespan role of autophagy and mitophagy
Biochimica et Biophysica Acta, 2019Co-Authors: Shuyi Wang, Jun Ren, Machender R KandadiAbstract:Abstract Increased age often leads to a gradual deterioration in cardiac geometry and contractile function although the precise mechanism remains elusive. Both Akt and AMPK play an essential role in the maintenance of cardiac homeostasis. This study examined the impact of ablation of Akt2 (the main cardiac isoform of Akt) and AMPKα2 on development of cardiac aging and the potential mechanisms involved with a focus on autophagy. Cardiac geometry, contractile, and intracellular Ca2+ properties were evaluated in young (4-month-old) and old (12-month-old) wild-type (WT) and Akt2-AMPK double knockout mice using echocardiography, IonOptix® edge-detection and fura-2 techniques. Levels of autophagy and mitophagy were evaluated using western blot. Our results revealed that increased age (12 months) did not elicit any notable effects on cardiac geometry, contractile function, morphology, ultrastructure, autophagy and mitophagy, although Akt2-AMPK double knockout predisposed aging-related unfavorable changes in geometry (heart weight, LVESD, LVEDD, cross-sectional area and interstitial fibrosis), TEM ultrastructure, and function (fractional shortening, peak shortening, maximal velocity of shortening/relengthening, time-to-90% relengthening, intracellular Ca2+ release and clearance rate). Double knockout of Akt2 and AMPK unmasked age-induced cardiac autophagy loss including decreased Atg5, Atg7, Beclin1, LC3BII-to-LC3BI ratio and increased p62. Double knockout of Akt2 and AMPK also unmasked age-related loss in mitophagy markers PTEN-induced putative kinase 1 (Pink1), Parkin, Bnip3, and FUNDC1, the mitochondrial biogenesis cofactor PGC-1α, and lysosomal biogenesis factor TFEB. In conclusion, our data indicate that Akt2-AMPK double ablation predisposes cardiac aging possibly related to compromised autophagy and mitophagy. This article is part of a Special Issue entitled: Genetic and epigenetic regulation of aging and longevity edited by Jun Ren & Megan Yingmei Zhang.
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pathogenesis of cardiac ischemia reperfusion injury is associated with ck2α disturbed mitochondrial homeostasis via suppression of FUNDC1 related mitophagy
Cell Death & Differentiation, 2018Co-Authors: Jun Ren, Hao Zhou, Jin Wang, Pingjun Zhu, Hong Zhu, Yundai ChenAbstract:Disturbed mitochondrial homeostasis contributes to the pathogenesis of cardiac ischemia reperfusion (IR) injury, although the underlying mechanism remains elusive. Here, we demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury. Increased CK2α was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2α knockout (CK2α CKO ) mice were protected against IR injury and mitochondrial damage. Functional assay indicated that CK2α enhanced the phosphorylation (inactivation) of FUN14 domain containing 1 (FUNDC1) via post-transcriptional modification at Ser13, thus effectively inhibiting mitophagy. Defective mitophagy failed to remove damaged mitochondria induced by IR injury, resulting in mitochondrial genome collapse, electron transport chain complex (ETC) inhibition, mitochondrial biogenesis arrest, cardiolipin oxidation, oxidative stress, mPTP opening, mitochondrial debris accumulation and eventually mitochondrial apoptosis. In contrast, loss of CK2α reversed the FUNDC1-mediated mitophagy, providing a survival advantage to myocardial tissue following IR stress. Interestingly, mice deficient in both CK2α and FUNDC1 failed to show protection against IR injury and mitochondrial damage through a mechanism possible attributed to lack of mitophagy. Taken together, our results confirmed that CK2α serves as a negative regulator of mitochondrial homeostasis via suppression of FUNDC1-required mitophagy, favoring the development of cardiac IR injury.
Quan Chen - One of the best experts on this subject based on the ideXlab platform.
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dynamic pgam5 multimers dephosphorylate bcl xl or FUNDC1 to regulate mitochondrial and cellular fate
Cell Death & Differentiation, 2020Co-Authors: Zhi Zhang, Linbo Chen, Yushan Zhu, Rui Chang, Hongcheng Cheng, Tian Zhao, Chuanmei Zhang, Qian Luo, Jialing Lin, Quan ChenAbstract:Mitochondria are highly dynamic organelles and respond to stress by changing their fission-fusion cycle, undergoing mitophagy, or releasing apoptotic proteins to initiate cell death. The molecular mechanisms that sense different stresses and coordinate distinct effectors still await full characterization. Here, we show that PGAM5, which exists in an equilibrium between dimeric and multimeric states, dephosphorylates BCL-xL to inhibit apoptosis or FUNDC1 to activate mitofission and mitophagy in response to distinct stresses. In vinblastine-treated cells, PGAM5 dephosphorylates BCL-xL at Ser62 to restore BCL-xL sequestration of BAX and BAK and thereby resistance to apoptosis. Selenite-induced oxidative stress increases the multimerization of PGAM5, resulting in its dissociation from BCL-xL, which causes increased BCL-xL phosphorylation and apoptosis. Once freed, the more multimeric and active PGAM5 dephosphorylates FUNDC1 to initiate mitofission and mitophagy. The reciprocal interaction of PGAM5 with FUNDC1 and BCL-xL, controlled by PGAM5 multimerization, serves as a molecular switch between mitofission/mitophagy and apoptosis.
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deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary induced obesity and metabolic syndrome
Autophagy, 2019Co-Authors: You Wang, Xiaohui Wang, Lei Liu, Quan Chen, Hui Chen, Dong LiuAbstract:There is overwhelming evidence for an association between impaired mitochondrial function and metabolic syndrome. Mitophagy, a process that selectively removes damaged mitochondria via a specialized form of autophagy, is essential for mitochondrial quality control (mitochondrial QC) and metabolic homeostasis. We thus addressed the potential role of defective mitophagy in the pathogenesis of metabolic disorders. Mice lacking FUNDC1, a newly characterized mitophagy receptor, develop more severe obesity and insulin resistance when fed a high-fat diet (HFD). Ablation of FUNDC1 results in defective mitophagy and impaired mitochondrial QC in vitro and in white adipose tissue (WAT). In addition, there is more pronounced WAT remodeling with more adipose tissue-associated macrophages infiltration, more M1 macrophage polarization and thus an elevated inflammatory response. Mechanistically, hyperactivation of MAPK/JNK leads to insulin insensitivity, which can be inhibited by knocking out Mapk8/Jnk1 in FUNDC1 KO mice. Our results demonstrate that dysregulated mitochondrial QC due to defective mitophagy receptor FUNDC1 links with metabolic disorders via MAPK signaling and inflammatory responses. Abbreviations: ATMs: adipose tissue macrophages; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HE HFD: high-fat diet; LIR: LC3-interacting region; mitochondrial QC: mitochondrial quality control; mito-ROS: mitochondrial ROS; mtDNA: mitochondrial DNA; RT-PCR: real-time-PCR; T2D: type 2 diabetes; WAT: white adipose tissue.
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a mitochondrial FUNDC1 hsc70 interaction organizes the proteostatic stress response at the risk of cell morbidity
The EMBO Journal, 2019Co-Authors: Yanhong Xue, Lei Liu, Ziheng Chen, Quan Chen, Yueying Wang, Weilin Zhang, Yushan Zhu, Guopeng Wang, Yiqun LiuAbstract:Both protein quality and mitochondrial quality are vital for the cellular activity, and impaired proteostasis and mitochondrial dysfunction are common etiologies of aging and age-related disorders. Here, we report that the mitochondrial outer membrane protein FUNDC1 interacts with the chaperone HSC70 to promote the mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or for formation of non-aggresomal mitochondrion-associated protein aggregates (MAPAs) upon proteasome inhibition in cultured human cells. Integrative approaches including csCLEM, Apex, and biochemical analysis reveal that MAPAs contain ubiquitinated cytosolic proteins, autophagy receptor p62, and mitochondrial proteins. MAPAs are segregated from mitochondria in a FIS1-dependent manner and can subsequently be degraded via autophagy. Although the FUNDC1/HSC70 pathway promotes the degradation of unfolded cytosolic proteins, excessive accumulation of unfolded proteins on the mitochondria prior to MAPA formation impairs mitochondrial integrity and activates AMPK, leading to cellular senescence. We suggest that human mitochondria organize cellular proteostatic response at the risk of their own malfunction and cell lethality.
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Mitochondria organize the cellular proteostatic response and promote cellular senescence
Shared Science Publishers OG, 2019Co-Authors: Lei Liu, Yushan Zhu, Quan ChenAbstract:Mitochondria have relatively independent protein quality control systems, including their own chaperones for protein folding and AAA proteases for protein degradation. Accumulating evidence has shown that cytosolic proteins and disease-causing misfolded proteins can be translocated into mitochondria and then impinge upon their function. It is important to understand the interplay between cellular proteostasis and mitochondria, as impaired proteostasis and mitochondrial dysfunction are causally linked with aging and age-related disorders. This review highlights our recent finding showing that the outer mitochondrial membrane protein FUNDC1, a previously reported mitophagy receptor, interacts with the chaperone protein HSC70 to mediate the mitochondrial translocation of cytosolic proteasomal substrates via the TOM/TIM complex into the mitochondrial matrix where they can be degraded by LONP1 protease. Excessive accumulation of unfolded proteins within mitochondria triggers the formation of Mitochondrion-Associated Protein Aggregates (MAPAs), which are subsequently autophagically degraded in a FUNDC1-dependent manner. We suggest that mitochondria actively organize the cellular proteostatic response and that the interaction between FUNDC1 and HSC70 may represent a new link between impaired proteostasis, mitochondrial dysfunction and cellular aging
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march5 FUNDC1 axis fine tunes hypoxia induced mitophagy
Autophagy, 2017Co-Authors: Ziheng Chen, Lei Liu, Sami Siraj, Quan ChenAbstract:Mitophagy is responsible for removal of damaged mitochondria and is therefore a fundamental process in mitochondrial quality control. Both ubiquitin-dependent and receptor-dependent pathways are considered to mediate mitophagy. These distinct mechanisms may be activated in response to distinct mitochondrial stresses. An intriguing question is whether and how crosstalk occurs between the distinct pathways to coordinate mitophagy. We have uncovered a striking piece of evidence to demonstrate that the mitophagy receptor FUNDC1 is a substrate of MARCH5, a mitochondrially localized E3 ubiquitin ligase. In response to hypoxia, MARCH5 degrades redundant FUNDC1 to fine-tune hypoxia-induced mitophagy, whereas ablation of MARCH5 leads to accumulation of FUNDC1 and an exaggerated mitophagic phenotype. Mechanistic studies demonstrate that hypoxic insult enhances the interaction of FUNDC1 with MARCH5, which ubiquitinates FUNDC1 at lysine 119 for subsequent degradation. MARCH5-based ubiquitination and degradation of FUNDC1 circumvents injudicious removal of cellular mitochondria. However, severe hypoxic stress leads to dephosphorylation of FUNDC1, increasing mitophagic flux.
Yundai Chen - One of the best experts on this subject based on the ideXlab platform.
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nr4a1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1 mediated mitophagy and promoting mff required mitochondrial fission by ck2α
Basic Research in Cardiology, 2018Co-Authors: Hao Zhou, Shunying Hu, Jin Wang, Sam Toan, Yundai ChenAbstract:Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.
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pathogenesis of cardiac ischemia reperfusion injury is associated with ck2α disturbed mitochondrial homeostasis via suppression of FUNDC1 related mitophagy
Cell Death & Differentiation, 2018Co-Authors: Jun Ren, Hao Zhou, Jin Wang, Pingjun Zhu, Hong Zhu, Yundai ChenAbstract:Disturbed mitochondrial homeostasis contributes to the pathogenesis of cardiac ischemia reperfusion (IR) injury, although the underlying mechanism remains elusive. Here, we demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury. Increased CK2α was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2α knockout (CK2α CKO ) mice were protected against IR injury and mitochondrial damage. Functional assay indicated that CK2α enhanced the phosphorylation (inactivation) of FUN14 domain containing 1 (FUNDC1) via post-transcriptional modification at Ser13, thus effectively inhibiting mitophagy. Defective mitophagy failed to remove damaged mitochondria induced by IR injury, resulting in mitochondrial genome collapse, electron transport chain complex (ETC) inhibition, mitochondrial biogenesis arrest, cardiolipin oxidation, oxidative stress, mPTP opening, mitochondrial debris accumulation and eventually mitochondrial apoptosis. In contrast, loss of CK2α reversed the FUNDC1-mediated mitophagy, providing a survival advantage to myocardial tissue following IR stress. Interestingly, mice deficient in both CK2α and FUNDC1 failed to show protection against IR injury and mitochondrial damage through a mechanism possible attributed to lack of mitophagy. Taken together, our results confirmed that CK2α serves as a negative regulator of mitochondrial homeostasis via suppression of FUNDC1-required mitophagy, favoring the development of cardiac IR injury.
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melatonin suppresses platelet activation and function against cardiac ischemia reperfusion injury via pparγ FUNDC1 mitophagy pathways
Journal of Pineal Research, 2017Co-Authors: Shunying Hu, Hao Zhou, Dandan Li, Nan Hu, Ying Zhang, Yundai ChenAbstract:Platelet activation is a major (patho-) physiological mechanism that underlies ischemia/reperfusion (I/R) injury. In this study, we explored the molecular signals for platelet hyperactivity and investigated the beneficial effects of melatonin on platelet reactivity in response to I/R injury. After reperfusion, peroxisome proliferator-activated receptor γ (PPARγ) was progressively downregulated in patients with acute myocardial infarction undergoing coronary artery bypass grafting (CABG) surgery and in mice with I/R injury model. Loss of PPARγ was closely associated with FUN14 domain containing 1 (FUNDC1) dephosphorylation and mitophagy activation, leading to increased mitochondrial electron transport chain complex (ETC) activity, enhanced mitochondrial respiratory function and elevated ATP production. The improved mitochondrial function strongly contributed to platelet aggregation, spreading, expression of P-selectin and final formation of micro-thromboses, eventually resulting in myocardial dysfunction and microvascular structural destruction. However, melatonin powerfully suppressed platelet activation via restoration of the PPARγ content in platelets, which subsequently blocked FUNDC1-required mitophagy, mitochondrial energy production, platelet hyperactivity and cardiac I/R injury. In contrast, genetic ablation of PPARγ in platelet abolished the beneficial effects of melatonin on mitophagy, mitochondrial ATP supply and platelet activation. Our results lay the foundation for the molecular mechanism of platelet activation in response to I/R injury and highlight that the manipulation of the PPARγ/FUNDC1/mitophagy pathway by melatonin could be a novel strategy for cardioprotection in the setting of cardiac I/R injury. This article is protected by copyright. All rights reserved.
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melatonin suppresses platelet activation and function against cardiac ischemia reperfusion injury via pparγ FUNDC1 mitophagy pathways
Journal of Pineal Research, 2017Co-Authors: Feng Cao, Jun Ren, Hao Zhou, Pingjun Zhu, Ying Zhang, Tianwen Han, Yundai ChenAbstract:Platelet activation is a major (patho-) physiological mechanism that underlies ischemia/reperfusion (I/R) injury. In this study, we explored the molecular signals for platelet hyperactivity and investigated the beneficial effects of melatonin on platelet reactivity in response to I/R injury. After reperfusion, peroxisome proliferator-activated receptor γ (PPARγ) was progressively downregulated in patients with acute myocardial infarction undergoing coronary artery bypass grafting (CABG) surgery and in mice with I/R injury model. Loss of PPARγ was closely associated with FUN14 domain containing 1 (FUNDC1) dephosphorylation and mitophagy activation, leading to increased mitochondrial electron transport chain complex (ETC.) activity, enhanced mitochondrial respiratory function, and elevated ATP production. The improved mitochondrial function strongly contributed to platelet aggregation, spreading, expression of P-selectin, and final formation of micro-thromboses, eventually resulting in myocardial dysfunction and microvascular structural destruction. However, melatonin powerfully suppressed platelet activation via restoration of the PPARγ content in platelets, which subsequently blocked FUNDC1-required mitophagy, mitochondrial energy production, platelet hyperactivity, and cardiac I/R injury. In contrast, genetic ablation of PPARγ in platelet abolished the beneficial effects of melatonin on mitophagy, mitochondrial ATP supply, and platelet activation. Our results lay the foundation for the molecular mechanism of platelet activation in response to I/R injury and highlight that the manipulation of the PPARγ/FUNDC1/mitophagy pathway by melatonin could be a novel strategy for cardioprotection in the setting of cardiac I/R injury.
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ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac ir injury
Redox biology, 2017Co-Authors: Hao Zhou, Feng Cao, Jun Ren, Shuyi Wang, Pingjun Zhu, Jun Guo, Yundai ChenAbstract:Abstract Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI). Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3 -/- ) mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria-mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI.
Aijun Sun - One of the best experts on this subject based on the ideXlab platform.
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alpha lipoic acid protects against pressure overload induced heart failure via aldh2 dependent nrf1 FUNDC1 signaling
Cell Death and Disease, 2020Co-Authors: Lei Yin, Xiaolei Sun, Zhen Dong, Aijun SunAbstract:Alpha-lipoic acid (α-LA), a well-known antioxidant, was proved to active ALDH2 in nitrate tolerance and diabetic animal model. However, the therapeutic advantage of α-LA for heart failure and related signaling pathway have not been explored. This study was designed to examine the role of α-LA-ALDH2 in heart failure injury and mitochondrial damage. ALDH2 knockout (ALDH2-/-) mice and primary neonatal rat cardiomyocytes (NRCMs) were subjected to assessment of myocardial function and mitochondrial autophagy. Our data demonstrated α-LA significantly reduced the degree of TAC-induced LV hypertrophy and dysfunction in wild-type mice, not in ALDH2-/- mice. In molecular level, α-LA significantly restored ALDH2 activity and expression as well as increased the expression of a novel mitophagy receptor protein FUNDC1 in wild-type TAC mice. Besides, we confirmed that ALDH2 which was activated by α-LA governed the activation of Nrf1-FUNDC1 cascade. Our data suggest that α-LA played a positive role in protecting the heart against adverse effects of chronic pressure overload.
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alpha lipoic acid protects against pressure overload induced heart failure via aldh2 dependent nrf1 FUNDC1 signaling
Social Science Research Network, 2019Co-Authors: Lei Yin, Xiaolei Sun, Zhen Dong, Aijun SunAbstract:Background: Acetaldehyde dehydrogenase 2 (ALDH2) could protect the heart against pressure overload-induced heart failure in mice. Alpha-lipoic acid (α-LA), a well-known antioxidant, was capable of activating ALDH2. However, impact of α-LA on pressure overload-induced heart failure remains unknown now. Methods: α-LA on pressure overload-induced heart failure were assessed using ALDH2 knockout (ALDH2-/-) mice and primary neonatal rat cardiomyocytes (NRCMs). TAC-induced left ventricular hypertrophy and contractile function were assessed by echocardiography and cell shortening/relengthening system. Heart histological measurement were using H&E, WGA, Masson’s trichrome, DHE and TUNEL. Mitochondrial mass and morphology were visualized using TEM. The target proteins and their interactions was investigated by bioinformatic analysis, luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Findings: In vivo, we found that supplement of α-LA significantly reduced transverse aortic constriction (TAC)-induced LV hypertrophy and dysfunction in wild-type mice, as evidenced by preserved LV ejection fraction, a more favorable histologic change and restoration of mitochondrial normality. Whereas, α-LA did not affect TAC induced LV hypertrophy and dysfunction in ALDH2 gene knockout (KO) mice. In molecular level, α-LA significantly restored ALDH2 activity and expression as well as upregulated the expression of FUN14 domain containing 1 (FUNDC1), an activator of hypoxia-induced mitophagy, in wild type TAC mice, again, these effects were not observed in ALDH2 gene KO mice undergoing TAC. In angiotensin II –induced hypertrophy in vitro model of neonatal rat cardiomyocytes (NRCMs), we confirmed that α-LA could activate ALDH2 and nuclear respiratory factor 1 (Nrf1) - FUNDC-1 cascade. Interpretation: These data supported the notion that α-LA treatment could protect the heart against adverse effects of chronic pressure overload via ALDH2-dependent Nrf1-FUNDC1 signaling pathway. Funding Statement: This work was supported by the National Science Fund for Distinguished Young Scholars to AS (81725002) and a grant of Innovative Research Groups of the National Natural Science Foundation of China (81521001). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: All of the mice experiments were performed under protocols approved by the Institutional Animal Care and Use Committee of the Fudan University.
