bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024‒01‒14
fourteen papers selected by
Gavin McStay, Liverpool John Moores University
  1. Varicella zoster virus glycoprotein E facilitates PINK1/Parkin-mediated mitophagy to evade STING and MAVS-mediated antiviral innate immunity.
  2. Herpesvirus lytic infection-induced mitophagy via viral interferon regulatory factor 1.
  3. Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.
  4. Arrestin-3 binds parkin and enhances parkin-dependent mitophagy.
  5. Cristae shaping and dynamics in mitochondrial function.
  6. Huntington disease affects mitochondrial network dynamics predisposing to pathogenic mtDNA mutations.
  7. Age and dietary restriction modulate mitochondrial quality in quadriceps femoris muscle of male mice.
  8. Mechanisms and therapeutic targets of mitophagy after intracerebral hemorrhage.
  9. Retracted: Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation.
  10. Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
  11. DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis.
  12. Breviscapine protects against pathological cardiac hypertrophy by targeting FOXO3a-mitofusin-1 mediated mitochondrial fusion.
  13. O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.
  14. CD30 protects EBV-positive diffuse large B-cell lymphoma cells against mitochondrial dysfunction through BNIP3-mediated mitophagy.
  1. Cell Death Dis. 2024 Jan 06. 15(1): 16
    Varicella zoster virus glycoprotein E facilitates PINK1/Parkin-mediated mitophagy to evade STING and MAVS-mediated antiviral innate immunity.
    Soo-Jin Oh, Je-Wook Yu, Jin-Hyun Ahn, Seok Tae Choi, Hosun Park, Jeanho Yun, Ok Sarah Shin.
      Viruses have evolved to control mitochondrial quality and content to facilitate viral replication. Mitophagy is a selective autophagy, in which the damaged or unnecessary mitochondria are removed, and thus considered an essential mechanism for mitochondrial quality control. Although mitophagy manipulation by several RNA viruses has recently been reported, the effect of mitophagy regulation by varicella zoster virus (VZV) remains to be fully determined. In this study, we showed that dynamin-related protein-1 (DRP1)-mediated mitochondrial fission and subsequent PINK1/Parkin-dependent mitophagy were triggered during VZV infection, facilitating VZV replication. In addition, VZV glycoprotein E (gE) promoted PINK1/Parkin-mediated mitophagy by interacting with LC3 and upregulating mitochondrial reactive oxygen species. Importantly, VZV gE inhibited MAVS oligomerization and STING translocation to disrupt MAVS- and STING-mediated interferon (IFN) responses, and PINK1/Parkin-mediated mitophagy was required for VZV gE-mediated inhibition of IFN production. Similarly, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-mediated mitophagy induction led to increased VZV replication but attenuated IFN production in a three-dimensional human skin organ culture model. Our results provide new insights into the immune evasion mechanism of VZV gE via PINK1/Parkin-dependent mitophagy.
    DOI:  https://doi.org/10.1038/s41419-023-06400-z
  2. Autophagy Rep. 2023 ;pii: 2281135. [Epub ahead of print]2(1):
    Herpesvirus lytic infection-induced mitophagy via viral interferon regulatory factor 1.
    Mai Tram Vo, Young Bong Choi.
      Viral control of mitochondria via mitophagy has a dampening effect on mitochondrion-mediated innate immune responses. We previously found that human herpesvirus 8 (HHV-8) could activate mitophagy via its lytic gene product vIRF-1 (viral interferon regulatory factor 1). Mechanistically, we previously demonstrated that vIRF-1 interacts with the mitophagic proteins BNIP3L (BCL2 interacting protein 3 like) and TUFM (Tu translation elongation factor, mitochondrial). Despite these significant findings, however, the precise molecular mechanisms underlying vIRF-1-activated mitophagy, particularly with core components of the autophagy machinery, remained to be fully elucidated. We recently reported that vIRF-1 binds preferentially and directly to GABARAPL1 (GABA type A receptor associated protein like 1) in a noncanonical manner, and this interaction is essential for virus-productive replication. Furthermore, we found that BNIP3L is a crucial factor that promotes vIRF-1 oligomerization and associated mitophagy activation, including GABARAPL1 interaction with vIRF-1 and TUFM dimerization. Together, our findings deepen our understanding of lytic infection-induced mitophagy and provide the key protein-protein interactions involved in vIRF-1-mediated mitophagy.
    Keywords:  BNIP3L; GABARAPL1; Human herpesvirus 8; Mitochondria; Mitophagy; Nix; TUFM; vIRF-1
    DOI:  https://doi.org/10.1080/27694127.2023.2281135
  3. Mol Cell. 2023 Dec 29. pii: S1097-2765(23)01031-6. [Epub ahead of print]
    Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.
    Sabine Poerschke, Silke Oeljeklaus, Luis Daniel Cruz-Zaragoza, Alexander Schenzielorz, Drishan Dahal, Hauke Sven Hillen, Hirak Das, Laura Sophie Kremer, Anusha Valpadashi, Mirjam Breuer, Johannes Sattmann, Ricarda Richter-Dennerlein, Bettina Warscheid, Sven Dennerlein, Peter Rehling.
      Cellular proteostasis requires transport of polypeptides across membranes. Although defective transport processes trigger cytosolic rescue and quality control mechanisms that clear translocases and membranes from unproductive cargo, proteins that are synthesized within mitochondria are not accessible to these mechanisms. Mitochondrial-encoded proteins are inserted cotranslationally into the inner membrane by the conserved insertase OXA1L. Here, we identify TMEM126A as a OXA1L-interacting protein. TMEM126A associates with mitochondrial ribosomes and translation products. Loss of TMEM126A leads to the destabilization of mitochondrial translation products, triggering an inner membrane quality control process, in which newly synthesized proteins are degraded by the mitochondrial iAAA protease. Our data reveal that TMEM126A cooperates with OXA1L in protein insertion into the membrane. Upon loss of TMEM126A, the cargo-blocked OXA1L insertase complexes undergo proteolytic clearance by the iAAA protease machinery together with its cargo.
    Keywords:  mitochondria; mitochondrial quality control; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.013
  4. J Neurochem. 2024 Jan 09.
    Arrestin-3 binds parkin and enhances parkin-dependent mitophagy.
    Chen Zheng, Kevin K Nguyen, Sergey A Vishnivetskiy, Vsevolod V Gurevich, Eugenia V Gurevich.
      Arrestins were discovered for their role in homologous desensitization of G-protein-coupled receptors (GPCRs). Later non-visual arrestins were shown to regulate several signaling pathways. Some of these pathways require arrestin binding to GPCRs, the regulation of others is receptor independent. Here, we demonstrate that arrestin-3 binds the E3 ubiquitin ligase parkin via multiple sites, preferentially interacting with its RING0 domain. Identification of the parkin domains involved suggests that arrestin-3 likely relieves parkin autoinhibition and/or stabilizes the enzymatically active "open" conformation of parkin. Arrestin-3 binding enhances ubiquitination by parkin of the mitochondrial protein mitofusin-1 and facilitates parkin-mediated mitophagy in HeLa cells. Furthermore, arrestin-3 and its mutant with enhanced parkin binding rescue mitofusin-1 ubiquitination and mitophagy in the presence of the Parkinson's disease-associated R275W parkin mutant, which is defective in both functions. Thus, modulation of parkin activity via arrestin-3 might be a novel strategy of anti-parkinsonian therapy.
    Keywords:  arrestin; mitochondria; mitophagy; parkin
    DOI:  https://doi.org/10.1111/jnc.16043
  5. J Cell Sci. 2024 Jan 01. pii: jcs260986. [Epub ahead of print]137(1):
    Cristae shaping and dynamics in mitochondrial function.
    Claire Caron, Giulia Bertolin.
      Mitochondria are multifunctional organelles of key importance for cell homeostasis. The outer mitochondrial membrane (OMM) envelops the organelle, and the inner mitochondrial membrane (IMM) is folded into invaginations called cristae. As cristae composition and functions depend on the cell type and stress conditions, they recently started to be considered as a dynamic compartment. A number of proteins are known to play a role in cristae architecture, such as OPA1, MIC60, LETM1, the prohibitin (PHB) complex and the F1FO ATP synthase. Furthermore, phospholipids are involved in the maintenance of cristae ultrastructure and dynamics. The use of new technologies, including super-resolution microscopy to visualize cristae dynamics with superior spatiotemporal resolution, as well as high-content techniques and datasets have not only allowed the identification of new cristae proteins but also helped to explore cristae plasticity. However, a number of open questions remain in the field, such as whether cristae-resident proteins are capable of changing localization within mitochondria, or whether mitochondrial proteins can exit mitochondria through export. In this Review, we present the current view on cristae morphology, stability and composition, and address important outstanding issues that might pave the way to future discoveries.
    Keywords:  Cristae; Cristae dynamics; High-content approaches; Mitochondria; Quantitative microscopy
    DOI:  https://doi.org/10.1242/jcs.260986
  6. Brain. 2024 Jan 09. pii: awae007. [Epub ahead of print]
    Huntington disease affects mitochondrial network dynamics predisposing to pathogenic mtDNA mutations.
    Andreas Neueder, Kerstin Kojer, Zhenglong Gu, Yiqin Wang, Tanja Hering, Sarah Tabrizi, Jan-Willem Taanman, Michael Orth.
      Huntington disease (HD) predominantly affects the brain causing a mixed movement disorder, cognitive decline and behavioural abnormalities. It also causes a peripheral phenotype involving skeletal muscle. Mitochondrial dysfunction has been reported in tissues of HD models, including skeletal muscle, and lymphoblasts and fibroblasts cultures from HD patients. Mutant huntingtin protein (mutHTT) expression can impair mitochondrial quality control and accelerate mitochondrial ageing. Here we obtained fresh human skeletal muscle, a post-mitotic tissue expressing the mutated HTT allele at physiological levels since birth, and primary cell lines from HTT CAG repeat expansion mutation carriers and matched healthy volunteers to examine whether such a mitochondrial phenotype exists in human HD. Using ultra-deep mitochondrial DNA (mtDNA) sequencing, we show an accumulation of mtDNA mutations affecting oxidative phosphorylation. Tissue proteomics indicate impairments in mtDNA maintenance with increased mitochondrial biogenesis of less efficient oxidative phosphorylation (lower complex I and IV activity). In full-length mutHTT expressing primary human cell lines, fission inducing mitochondrial stress resulted in normal mitophagy. In contrast, expression of high levels of N-terminal mutHTT fragments promoted mitochondrial fission and resulted in slower, less dynamic mitophagy. Expression of high levels of mutHTT fragments due to somatic nuclear HTT CAG instability can thus affect mitochondrial network dynamics and mitophagy leading to pathogenic mtDNA mutations. We show that life-long expression of mutant HTT causes a mitochondrial phenotype indicative of mtDNA instability in fresh post-mitotic human skeletal muscle. Thus, genomic instability may not be limited to nuclear DNA where it results in somatic expansion of HTT CAG repeat length in particularly vulnerable cells, such as striatal neurons. In addition to efforts targeting the causative mutation promoting mitochondrial health may be a complementary strategy in treating diseases with DNA instability, such as HD.
    Keywords:  DNA instability; huntingtin fragments; mitochondrial fission; mitophagy; proteomics; ultra-deep mitochondrial DNA sequencing
    DOI:  https://doi.org/10.1093/brain/awae007
  7. Biogerontology. 2024 Jan 06.
    Age and dietary restriction modulate mitochondrial quality in quadriceps femoris muscle of male mice.
    Ting-Rui Zhang, Chun-Hsien Chiang, Tzu-Chieh Hsu, Chih-Yun Wang, Ching-Yi Chen.
      Dietary restriction (DR) is a potential intervention for ameliorating ageing-related damages. Mitochondrial quality control is the key mechanism for regulating cellular functions in skeletal muscle. This study aimed to explore the effect of age and DR on the homeostasis of mitochondrial quality control in skeletal muscle. To study the effect of age on mitochondrial homeostasis, young (3 months old) male C57BL/6J mice were fed ad libitum (AL) until 7 (Young), 14 (Middle), and 19 months (Aged) of age. For the DR intervention, 60% of AL intake was given to the mice at 3 months of age until they reached 19 months of age (16 months). The quadriceps femoris muscle was collected for further analysis. Significant changes in the skeletal muscle were noticed during the transition between middle age and the elderly stages. An accumulation of collagen was observed in the muscle after middle age. Compared with the Middle muscle, Aged muscle displayed a greater expression of VDAC, and lower expressions of mitochondrial dynamic proteins and OXPHOS proteins. The DR intervention attenuated collagen content and elongated the sarcomere length in the skeletal muscle during ageing. In addition, DR adjusted the abnormalities in mitochondrial morphology in the Aged muscle. DR downregulated VDAC expression, but upregulated OPA1 and DRP1 expressions. Taken together, greater pathological changes were noticed in the skeletal muscle during ageing, especially in the transition between middle age and the elderly, whereas early-onset DR attenuated the muscular ageing via normalising partial functions of mitochondria.
    Keywords:  Ageing; Dietary restriction; Mitochondrial homeostasis; Quadriceps femoris muscle
    DOI:  https://doi.org/10.1007/s10522-023-10086-3
  8. Heliyon. 2024 Jan 15. 10(1): e23941
    Mechanisms and therapeutic targets of mitophagy after intracerebral hemorrhage.
    Qinghua Huang, Xiaoqin Yu, Peijie Fu, Moxin Wu, Xiaoping Yin, Zhiying Chen, Manqing Zhang.
      Mitochondria are dynamic organelles responsible for cellular energy production. In addition to regulating energy homeostasis, mitochondria are responsible for calcium homeostasis, clearance of damaged organelles, signaling, and cell survival in the context of injury and pathology. In stroke, the mechanisms underlying brain injury secondary to intracerebral hemorrhage are complex and involve cellular hypoxia, oxidative stress, inflammatory responses, and apoptosis. Recent studies have shown that mitochondrial damage and autophagy are essential for neuronal metabolism and functional recovery after intracerebral hemorrhage, and are closely related to inflammatory responses, oxidative stress, apoptosis, and other pathological processes. Because hypoxia and inflammatory responses can cause secondary damage after intracerebral hemorrhage, the restoration of mitochondrial function and timely clearance of damaged mitochondria have neuroprotective effects. Based on studies on mitochondrial autophagy (mitophagy), cellular inflammation, apoptosis, ferroptosis, the BNIP3 autophagy gene, pharmacological and other regulatory approaches, and normobaric oxygen (NBO) therapy, this article further explores the neuroprotective role of mitophagy after intracerebral hemorrhage.
    Keywords:  Autophagy; BNIP3; Hypoxia; Inflammation and oxidative stress; Intracerebral hemorrhage; Mitophagy
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e23941
  9. Biomed Res Int. 2023 ;2023 9898164
    Retracted: Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation.
    BioMed Research International.
      [This retracts the article DOI: 10.1155/2022/7436577.].
    DOI:  https://doi.org/10.1155/2023/9898164
  10. EMBO J. 2024 Jan 11.
    Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
    Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Kaitlyn Vitangcol, Greg A Timblin, Kaoru Saijo, Biao Wang, Güneş Parlakgül, Ana Paula Arruda, Andreas Stahl.
      Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.
    Keywords:  Brown Adipose Tissue; Coenzyme Q; FGF21; Mitochondrial Unfolded Protein Response; Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-023-00008-x
  11. Acta Pharmacol Sin. 2024 Jan 10.
    DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis.
    Ming Yang, Yan Liu, Shi-Lu Luo, Chong-Bin Liu, Na Jiang, Chen-Rui Li, Hao Zhao, Ya-Chun Han, Wei Chen, Li Li, Lin Sun.
      Renal fibrosis is the final pathological change in renal disease, and aging is closely related to renal fibrosis. Mitochondrial dysfunction has been reported to play an important role in aging, but the exact mechanism remains unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is mainly located in mitochondria and plays an important role in regulating mitochondrial function and endoplasmic reticulum (ER) stress. However, the role of DsbA-L in renal aging has not been reported. In this study, we showed a reduction in DsbA-L expression, the disruption of mitochondrial function and an increase in fibrosis in the kidneys of 12- and 24-month-old mice compared to young mice. Furthermore, the deterioration of mitochondrial dysfunction and fibrosis were observed in DsbA-L-/- mice with D-gal-induced accelerated aging. Transcriptome analysis revealed a decrease in Flt4 expression and inhibition of the PI3K-AKT signaling pathway in DsbA-L-/- mice compared to control mice. Accelerated renal aging could be alleviated by an AKT agonist (SC79) or a mitochondrial protector (MitoQ) in mice with D-gal-induced aging. In vitro, overexpression of DsbA-L in HK-2 cells restored the expression of Flt4, AKT pathway factors, SP1 and PGC-1α and alleviated mitochondrial damage and cell senescence. These beneficial effects were partially blocked by inhibiting Flt4. Finally, activating the AKT pathway or improving mitochondrial function with chemical reagents could alleviate cell senescence. Our results indicate that the DsbA-L/AKT/PGC-1α signaling pathway could be a therapeutic target for age-related renal fibrosis and is associated with mitochondrial dysfunction.
    Keywords:  DsbA-L; Flt4; aging; kidney; mitochondria
    DOI:  https://doi.org/10.1038/s41401-023-01216-1
  12. Free Radic Biol Med. 2024 Jan 06. pii: S0891-5849(24)00007-8. [Epub ahead of print]
    Breviscapine protects against pathological cardiac hypertrophy by targeting FOXO3a-mitofusin-1 mediated mitochondrial fusion.
    Xiaobing Lin, Ming-Zhou Fei, An-Xian Huang, Liu Yang, Ze-Jie Zeng, Wen Gao.
      Forkhead box O3a (FOXO3a)-mediated mitochondrial dysfunction plays a pivotal effect on cardiac hypertrophy and heart failure (HF). However, the role and underlying mechanisms of FOXO3a, regulated by breviscapine (BRE), on mitochondrial function in HF therapy remain unclear. This study reveals that BRE-induced nuclear translocation of FOXO3a facilitates mitofusin-1 (MFN-1)-dependent mitochondrial fusion in cardiac hypertrophy and HF. BRE effectively promotes cardiac function and ameliorates cardiac remodeling in pressure overload-induced mice. In addition, BRE mitigates phenylephrine (PE)-induced cardiac hypertrophy in cardiomyocytes and fibrosis remodeling in fibroblasts by inhibiting ROS production and promoting mitochondrial fusion, respectively. Transcriptomics analysis underscores the close association between the FOXO pathway and the protective effect of BRE against HF, with FOXO3a emerging as a potential target of BRE. BRE potentiates the nuclear translocation of FOXO3a by attenuating its phosphorylation, other than its acetylation in cardiac hypertrophy. Mechanistically, over-expression of FOXO3a significantly inhibits cardiac hypertrophy and mitochondrial injury by promoting MFN-1-mediated mitochondrial fusion. Furthermore, BRE demonstrates its ability to substantially curb cardiac hypertrophy, reduce mitochondrial ROS production, and enhance MFN-1-mediated mitochondrial fusion through a FOXO3a-dependent mechanism. In conclusion, nuclear FOXO3a translocation induced by BRE presents a successful therapeutic avenue for addressing cardiac hypertrophy and HF through promoting MFN-1-dependent mitochondrial fusion.
    Keywords:  Breviscapine; Forkhead box O3a; Heart failure; Mitochondrial fusion; Mitofusin-1; Myocardial remodelling
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.007
  13. Front Aging Neurosci. 2023 ;15 1326127
    O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.
    Ibtihal M Alghusen, Marisa S Carman, Heather Wilkins, Sophiya John Ephrame, Amy Qiang, Wagner B Dias, Halyna Fedosyuk, Aspin R Denson, Russell H Swerdlow, Chad Slawson.
      Background: Accumulation of mitochondrial dysfunctional is a hallmark of age-related neurodegeneration including Alzheimer's disease (AD). Impairment of mitochondrial quality control mechanisms leading to the accumulation of damaged mitochondria and increasing neuronal stress. Therefore, investigating the basic mechanisms of how mitochondrial homeostasis is regulated is essential. Herein, we investigate the role of O-GlcNAcylation, a single sugar post-translational modification, in controlling mitochondrial stress-induced transcription factor Activating Transcription Factor 4 (ATF4). Mitochondrial dysfunction triggers the integrated stress response (ISRmt), in which the phosphorylation of eukaryotic translation initiation factor 2α results in the translation of ATF4.Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma and HeLa cell-lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) on ISRmt using biochemical analyses.
    Results: We show that TMG elevates ATF4 protein levels upon mitochondrial stress in SH-SY5Y neuroblastoma and HeLa cell-lines. An indirect downstream target of ATF4 mitochondrial chaperone glucose-regulated protein 75 (GRP75) is significantly elevated. Interestingly, knock-down of O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, in SH-SY5Y increases ATF4 protein and mRNA expression. Additionally, ATF4 target gene Activating Transcription Factor 5 (ATF5) is significantly elevated at both the protein and mRNA level. Brains isolated from TMG treated mice show elevated levels of ATF4 and GRP75. Importantly, ATF4 occupancy increases at the ATF5 promoter site in brains isolated from TMG treated mice suggesting that O-GlcNAc is regulating ATF4 targeted gene expression. Interestingly, ATF4 and GRP75 are not induced in TMG treated familial Alzheimer's Disease mice model. The same results are seen in a human in vitro model of AD.
    Conclusion: Together, these results indicate that in healthy conditions, O-GlcNAc regulates the ISRmt through regulating ATF4, while manipulating O-GlcNAc in AD has no effect on ISRmt.
    Keywords:  Alzheimer’s disease; O-GlcNAc; activating transcription factor 4 (ATF4); integrated stress response; mitochondrial stress
    DOI:  https://doi.org/10.3389/fnagi.2023.1326127
  14. Cancer Lett. 2024 Jan 09. pii: S0304-3835(24)00010-7. [Epub ahead of print] 216616
    CD30 protects EBV-positive diffuse large B-cell lymphoma cells against mitochondrial dysfunction through BNIP3-mediated mitophagy.
    Wei-Ting Wang, Tong-Yao Xing, Kai-Xin Du, Wei Hua, Jing-Ran Guo, Zi-Wen Duan, Yi-Fan Wu, Jia-Zhu Wu, Yue Li, Hua Yin, Hao-Rui Shen, Li Wang, Jian-Yong Li, Jin-Hua Liang, Wei Xu.
      Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (EBV+ DLBCL) predicts poor prognosis and CD30 expression aggravates the worse consequences. Here, we reported that CD30 positivity was an independent prognostic indicator in EBV+ DLBCL patients in a retrospective cohort study. We harnessed CRISPR/Cas9 editing to engineer the first loss-of-function models of CD30 deficiency to identify that CD30 was critical for EBV+ DLBCL growth and survival. We established a pathway that EBV infection mediated CD30 expression through EBV-encoded latent membrane protein 1 (LMP1), which involved NF-κB signaling. CRISPR CD30 knockout significantly repressed BCL2 interacting protein 3 (BNIP3) expression and co-IP assay indicated a binding between CD30 and BNIP3. Moreover, silencing of CD30 induced mitochondrial dysfunction and suppressed mitophagy, resulting in the accumulation of damaged mitochondria by depressing BNIP3 expression. Additionally, CRISPR BNIP3 knockout caused proliferation defects and increased sensitivity to apoptosis. All the findings reveal a strong relationship between mitophagy and adverse prognosis of EBV+ DLBCL and discover a new regulatory mechanism of BNIP3-mediated mitophagy, which may help develop effective treatment regimens with anti-CD30 antibody brentuximab vedotin to improve the prognosis of CD30+ EBV+ DLBCL patients.
    Keywords:  BNIP3; CD30; EBV-Positive diffuse large B-Cell lymphoma; LMP1; Mitophagy
    DOI:  https://doi.org/10.1016/j.canlet.2024.216616
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