bims-mikwok 2024-03-10 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒03‒10
twenty-six papers selected by
Gavin McStay, Liverpool John Moores University

The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
An unexpected journey for BNIP3.
The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress.
ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.
Quercetin inhibits necroptosis in cardiomyocytes after ischemia-reperfusion via DNA-PKcs-SIRT5-orchestrated mitochondrial quality control.
CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.
Non-cytopathic bovine viral diarrhea virus (BVDV) inhibits innate immune responses via induction of mitophagy.
SIRT1-Rab7 axis attenuates NLRP3 and STING activation through late endosomal-dependent mitophagy during sepsis-induced acute lung injury.
PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae.
[Role of mitochondrial dynamics in diabetic cardiomyopathy and regulatory mechanisms].
[Research progress on the role of TANK-binding kinase 1 in PINK1/Parkin-dependent and -independent mitophagy].
[Regulatory mechanisms of mitochondrial dynamics and its emerging role in renal pathophysiology].
Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.
Advances in the study of mitophagy in osteoarthritis.
Cuproptotic nanoinducer-driven proteotoxic stress potentiates cancer immunotherapy by activating the mtDNA-cGAS-STING signaling.
C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis.
Defective Mitophagy Impairs Response to Inflammatory Activation of Macrophage-Like Cells.
Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury.
CD62E- and ROS-Responsive ETS Improves Cartilage Repair by Inhibiting Endothelial Cell Activation through OPA1-Mediated Mitochondrial Homeostasis.
Drp1: Focus on Diseases Triggered by the Mitochondrial Pathway.
Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases.
NDUFS4 regulates cristae remodeling in diabetic kidney disease.
LncRNA OIP5-AS1 promotes mitophagy to alleviate osteoarthritis by up-regulating PPAR-γ to activate AMPK/Akt/mTOR pathway.
Apigenin ameliorates genitourinary dysfunction in a type 1 diabetic rat model via Drp1 modulation.
[Retracted] Liraglutide repairs the infarcted heart: The role of the SIRT1/Parkin/mitophagy pathway.
Mitochondrial fission enhances IL-6-induced metastatic potential in ovarian cancer via ERK1/2 activation.

Semin Cell Dev Biol. 2024 Mar 01. pii: S1084-9521(24)00022-3. [Epub ahead of print]161-162 1-19

The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.

Alice Lacombe, Luca Scorrano.

  The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.

Keywords:  Mitochondria; autophagy; diseases; fusion-fission; mitophagy

DOI:  https://doi.org/10.1016/j.semcdb.2024.02.001
Autophagy. 2024 Mar 06. 1-2

An unexpected journey for BNIP3.

José M Delgado, Christopher J Shoemaker.

  Mitophagy is a cellular process that enables the selective degradation of damaged, dysfunctional, or superfluous mitochondria. During mitophagy, specific proteins recognize and tag mitochondria for degradation. These tagged mitochondria are engulfed by specialized structures called phagophores that then mature into autophagosomes/mitophagosomes. Mitophagosomes subsequently transport their mitochondrial cargo to lysosomes, where the mitochondria are broken down and recycled. While the PINK1-PRKN-dependent mitophagy pathway is well understood, mitophagy can also occur independently of this pathway. BNIP3 and BNIP3L/NIX, paralogous membrane proteins on the outer mitochondrial membrane (OMM), serve as ubiquitin-independent mitophagy receptors. Historically, BNIP3 regulation was thought to be primarily transcriptional through HIF1A (hypoxia inducible factor 1 subunit alpha). However, recent work has revealed a significant post-translational dimension, highlighting the strong role of the ubiquitin-proteasome system (UPS) in BNIP3 regulation. With these emerging concepts in mind, we aimed to develop a unified understanding of how steady-state levels of BNIP3 are established and maintained and how this regulation governs underlying cell physiology.

Keywords:  BNIP3; EMC; ER membrane protein complex; NIX; membrane trafficking; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2312038
Exp Mol Med. 2024 Mar 05.

The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress.

Dae Jin Jeong, Jee-Hyun Um, Young Yeon Kim, Dong Jin Shin, Sangwoo Im, Kang-Min Lee, Yun-Hee Lee, Dae-Sik Lim, Donghoon Kim, Jeanho Yun.

Mitophagy induction upon mitochondrial stress is critical for maintaining mitochondrial homeostasis and cellular function. Here, we found that Mst1/2 (Stk3/4), key regulators of the Hippo pathway, are required for the induction of mitophagy under various mitochondrial stress conditions. Knockdown of Mst1/2 or pharmacological inhibition by XMU-MP-1 treatment led to impaired mitophagy induction upon CCCP and DFP treatment. Mechanistically, Mst1/2 induces mitophagy independently of the PINK1-Parkin pathway and the canonical Hippo pathway. Moreover, our results suggest the essential involvement of BNIP3 in Mst1/2-mediated mitophagy induction upon mitochondrial stress. Notably, Mst1/2 knockdown diminishes mitophagy induction, exacerbates mitochondrial dysfunction, and reduces cellular survival upon neurotoxic stress in both SH-SY5Y cells and Drosophila models. Conversely, Mst1 and Mst2 expression enhances mitophagy induction and cell survival. In addition, AAV-mediated Mst1 expression reduced the loss of TH-positive neurons, ameliorated behavioral deficits, and improved mitochondrial function in an MPTP-induced Parkinson's disease mouse model. Our findings reveal the Mst1/2-BNIP3 regulatory axis as a novel mediator of mitophagy induction under conditions of mitochondrial stress and suggest that Mst1/2 play a pivotal role in maintaining mitochondrial function and neuronal viability in response to neurotoxic treatment.

DOI: https://doi.org/10.1038/s12276-024-01198-y
Cell Death Dis. 2024 Mar 02. 15(3): 184

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.

Palamou Das, Oishee Chakrabarti.

Dynamin related protein 1 (DRP1), a pivotal mitochondrial fission protein, is post-translationally modified by multiple mechanisms. Here we identify a new post-translational modification of DRP1 by the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). DRP1 ISGylation is mediated by ISG15 E3 ligase, HERC5; this promotes mitochondrial fission. DeISGylation of DRP1 however leads to hyperfusion. Heterologous expression of SARS-CoV2 PLpro, a deISGylating enzyme, results in similar mitochondrial filamentation, significant decrease in total DRP1 protein levels and efflux of mtDNA. We report that deISGylated DRP1 gets ubiquitylated and degraded by TRIM25, instead of PARKIN and MITOL. While the cytosolic pool of DRP1 is primarily ISGylated, both mitochondrial and cytosolic fractions may be ubiquitylated. It is known that phosphorylation of DRP1 at S616 residue regulates its mitochondrial localisation; we show that ISGylation of phospho-DRP1 (S616) renders fission competence at mitochondria. This is significant because DRP1 ISGylation affects its functionality and mitochondrial dynamics in Alzheimer's disease pathophysiology.

DOI: https://doi.org/10.1038/s41419-024-06543-7
Phytother Res. 2024 Mar 06.

Quercetin inhibits necroptosis in cardiomyocytes after ischemia-reperfusion via DNA-PKcs-SIRT5-orchestrated mitochondrial quality control.

Xing Chang, Qin Zhang, Yu Huang, Jinfeng Liu, Yanli Wang, Xuanke Guan, Qiaomin Wu, Zhiming Liu, Ruxiu Liu.

  We investigated the mechanism by which quercetin preserves mitochondrial quality control (MQC) in cardiomyocytes subjected to ischemia-reperfusion stress. An enzyme-linked immunosorbent assay was employed in the in vivo experiments to assess myocardial injury markers, measure the transcript levels of SIRT5/DNAPK-cs/MLKL during various time intervals of ischemia-reperfusion, and observe structural changes in cardiomyocytes using transmission electron microscopy. In in vitro investigations, adenovirus transfection was employed to establish a gene-modified model of DNA-PKcs, and primary cardiomyocytes were obtained from a mouse model with modified SIRT5 gene. Reverse transcription polymerase chain reaction, laser confocal microscopy, immunofluorescence localization, JC-1 fluorescence assay, Seahorse energy analysis, and various other assays were applied to corroborate the regulatory influence of quercetin on the MQC network in cardiomyocytes after ischemia-reperfusion. In vitro experiments demonstrated that ischemia-reperfusion injury caused changes in the structure of the myocardium. It was seen that quercetin had a beneficial effect on the myocardial tissue, providing protection. As the ischemia-reperfusion process continued, the levels of DNA-PKcs/SIRT5/MLKL transcripts were also found to change. In vitro investigations revealed that quercetin mitigated cardiomyocyte injury caused by mitochondrial oxidative stress through DNA-PKcs, and regulated mitophagy and mitochondrial kinetics to sustain optimal mitochondrial energy metabolism levels. Quercetin, through SIRT5 desuccinylation, modulated the stability of DNA-PKcs, and together they regulated the "mitophagy-unfolded protein response." This preserved the integrity of mitochondrial membrane and genome, mitochondrial dynamics, and mitochondrial energy metabolism. Quercetin may operate synergistically to oversee the regulation of mitophagy and the unfolded protein response through DNA-PKcs-SIRT5 interaction.

Keywords:  SIRT5-DNA-PKcs; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy; necroptosis; quercetin

DOI:  https://doi.org/10.1002/ptr.8177
Autophagy. 2024 Mar 06. 1-25

CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.

Prakash P Praharaj, Srimanta Patra, Amruta Singh, Debasna P Panigrahi, Hwa Y Lee, Mohammad F Kabir, Muhammad K Hossain, Samir K Patra, Birija S Patro, Shankargouda Patil, Daniel J Klionsky, Han J Chae, Sujit K Bhutia.

  Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU acts as an adaptor protein that coordinately interacts with BAX and LC3 recruiting autophagic machinery around damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes resulting in reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (siPPARGC1A) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer.

Keywords:  Clusterin; PPARGC1A/PGC1α; mitochondrial biogenesis; mitophagy; mitophagy-associated cell death

DOI:  https://doi.org/10.1080/15548627.2024.2309904
Vet Res. 2024 Mar 05. 55(1): 27

Non-cytopathic bovine viral diarrhea virus (BVDV) inhibits innate immune responses via induction of mitophagy.

Zhijun Li, Ying Zhang, Bao Zhao, Qinghong Xue, Chunjiang Wang, Siyu Wan, Jingyu Wang, Xiwen Chen, Xuefeng Qi.

  Bovine viral diarrhea virus (BVDV) belongs to the genus Pestivirus within the family Flaviviridae. Mitophagy plays important roles in virus-host interactions. Here, we provide evidence that non-cytopathic (NCP) BVDV shifts the balance of mitochondrial dynamics toward fission and induces mitophagy to inhibit innate immune responses. Mechanistically, NCP BVDV triggers the translocation of dynamin-related protein (Drp1) to mitochondria and stimulates its phosphorylation at Ser616, leading to mitochondrial fission. In parallel, NCP BVDV-induced complete mitophagy via Parkin-dependent pathway contributes to eliminating damaged mitochondria to inhibit MAVS- and mtDNA-cGAS-mediated innate immunity responses, mtROS-mediated inflammatory responses and apoptosis initiation. Importantly, we demonstrate that the LIR motif of ERNS is essential for mitophagy induction. In conclusion, this study is the first to show that NCP BVDV-induced mitophagy plays a central role in promoting cell survival and inhibiting innate immune responses in vitro.

Keywords:  BVDV; MAVS; PINK1-Parkin; cGAS; innate immunity; mitophagy; persistent infection

DOI:  https://doi.org/10.1186/s13567-024-01284-z
Int J Surg. 2024 Mar 04.

SIRT1-Rab7 axis attenuates NLRP3 and STING activation through late endosomal-dependent mitophagy during sepsis-induced acute lung injury.

Tao Jiang, Enran Liu, Zhiyuan Li, Congmin Yan, Xiaoyun Zhang, Jingting Guan, Yuanbo Zhan, Bo Zhao, Wengang Ding.

BACKGROUND: Acute lung injury (ALI) is a leading cause of mortality in patients with sepsis due to proinflammatory endothelial changes and endothelial permeability defects. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of sepsis-induced ALI. Although mitophagy regulation of mitochondrial quality is well recognized, little is known about its role in lung ECs during sepsis-induced ALI. Sirtuin 1 (SIRT1) is a histone protein deacetylase involved in inflammation, mitophagy, and cellular senescence. Here, the authors show a type of late endosome-dependent mitophagy that inhibits NLRP3 and STING activation through SIRT1 signaling during sepsis-induced ALI.METHODS: C57BL/6J male mice with or without administration of the SIRT1 inhibitor EX527 in the CLP model and lung ECs in vitro were developed to identify mitophagy mechanisms that underlie the cross-talk between SIRT1 signaling and sepsis-induced ALI.
RESULTS: SIRT1 deficient mice exhibited exacerbated sepsis-induced ALI. Knockdown of SIRT1 interfered with mitophagy through late endosome Rab7, leading to the accumulation of damaged mitochondria and inducing excessive mitochondrial reactive oxygen species (mtROS) generation and cytosolic release of mitochondrial DNA (mtDNA), which triggered NLRP3 inflammasome and the cytosolic nucleotide sensing pathways (STING) over-activation. Pharmacological inhibition of STING and NLRP3 in vivo or genetic knockdown in vitro reversed SIRT1 deficiency mediated endothelial permeability defects and endothelial inflammation in sepsis-induced ALI. Moreover, activation of SIRT1 with SRT1720 in vivo or overexpression of SIRT1 in vitro protected against sepsis-induced ALI.
CONCLUSION: These findings suggest that SIRT1 signaling is essential for restricting STING and NLRP3 hyperactivation by promoting endosomal-mediated mitophagy in lung ECs, providing potential therapeutic targets for treating sepsis-induced ALI.

DOI: https://doi.org/10.1097/JS9.0000000000001215
Nat Commun. 2024 Mar 04. 15(1): 1967

PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae.

Wenhao Li, Hongwei Zhu, Jinzhu Chen, Binglu Ru, Qin Peng, Jianqiang Miao, Xili Liu.

Host-derived reactive oxygen species (ROS) are an important defense means to protect against pathogens. Although mitochondria are the main intracellular targets of ROS, how pathogens regulate mitochondrial physiology in response to oxidative stress remains elusive. Prohibitin 2 (PHB2) is an inner mitochondrial membrane (IMM) protein, recognized as a mitophagy receptor in animals and fungi. Here, we find that an ANK and FYVE domain-containing protein PsAF5, is an adapter of PsPHB2, interacting with PsATG8 under ROS stress. Unlike animal PHB2 that can recruit ATG8 directly to mitochondria, PsPHB2 in Phytophthora sojae cannot recruit PsATG8 to stressed mitochondria without PsAF5. PsAF5 deletion impairs mitophagy under ROS stress and increases the pathogen's sensitivity to H2O2, resulting in the attenuation of P. sojae virulence. This discovery of a PsPHB2-PsATG8 adapter (PsAF5) in plant-pathogenic oomycetes reveals that mitophagy induction by IMM proteins is conserved in eukaryotes, but with differences in the details of ATG8 recruitment.

DOI: https://doi.org/10.1038/s41467-024-46290-z
Sheng Li Xue Bao. 2024 Feb 25. 76(1): 128-136

[Role of mitochondrial dynamics in diabetic cardiomyopathy and regulatory mechanisms].

Huan Yue, De-Ma De, Ming-Ge Ding, Feng Fu.

Cardiovascular complications are the leading cause of death in diabetic patients. Among them, diabetic cardiomyopathy (DCM) is a type of specific cardiomyopathy excluding myocardial damage caused by hypertension and coronary heart disease. It is characterized by abnormal metabolism of cardiomyocytes and gradual decline of cardiac function. The clinical manifestations of DCM are impaired diastolic function in early stage and impaired systolic function in late stage. Eventually it developed into heart failure. Mitochondria are the main organelles that provide energy in cardiomyocytes. Mitochondrial dynamics refers to the dynamic process of mitochondrial fusion and fission, which is an important approach for mitochondrial quality control. Mitochondrial dynamics plays a crucial role in maintaining mitochondrial homeostasis and cardiac function. The proteins that regulate mitochondrial fission are mainly Drp1 and its receptors, Fis1, MFF, MiD49 and MiD51. The protein that performs mitochondrial outer membrane fusion is Mfn1/2, and the inner membrane fusion protein is Opa1. This paper reviews recent progress on mitochondrial dynamics in DCM. The main contents are as follows: mitochondrial dynamics imbalance in both type 1 and 2 DCM is manifested as increased fission and inhibited fusion. The molecular mechanism of the former is mainly associated with up-regulated Drp1 and down-regulated Opa1, while the molecular mechanism of the latter is mainly associated with up-regulated Drp1 and down-regulated Mfn1/2. Increased mitochondrial fission and inhibited fusion can lead to mitochondrial dysfunction and promote the development of DCM. The active ingredients of the traditional Chinese medicine such as punicalagin, paeonol and endogenous substance melatonin can improve mitochondrial function and alleviate the symptoms of DCM by inhibiting mitochondrial fission or promoting mitochondrial fusion. This article is helpful to further understand the role and mechanism of mitochondrial dynamics in DCM, and provide new treatment methods and intervention strategies for clinical DCM patients based on mitochondrial dynamics.
Sheng Li Xue Bao. 2024 Feb 25. 76(1): 161-172

[Research progress on the role of TANK-binding kinase 1 in PINK1/Parkin-dependent and -independent mitophagy].

Hao Deng, Zhi Xia, Hua-Yu Shang.

Mitophagy is a process that selectively removes excess or damaged mitochondria and plays an important role in regulating intracellular mitochondrial mass and maintaining mitochondrial energy metabolism. TANK-binding kinase 1 (TBK1) is a multifunctional serine/threonine protein kinase, which is involved in the regulation of PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent and -independent mitophagy. Recent studies have shown that TBK1 phosphorylates the autophagy related proteins, such as optineurin (OPTN), p62/sequestosome-1, Ras-related GTP binding protein 7 (Rab7), and mediates the binding of nuclear dot protein 52 (NDP52) to UNC-51 like autophagy activating kinase 1 (ULK1) complex, as well as the binding of TAX1-binding protein 1 (TAX1BP1) to microtubule-associated protein 1 light chain 3 (LC3), thereby enhancing PINK1/Parkin-dependent mitophagy. In addition, TBK1 is a direct substrate of AMP-activated protein kinase (AMPK)/ULK1 pathway, and its activation phosphorylates dynamin-related protein 1 (Drp1) and Rab7 to promote PINK1/Parkin-independent mitophagy. This article reviews the role and mechanism of TBK1 in regulating PINK1/Parkin-dependent and -independent mitophagy.
Sheng Li Xue Bao. 2024 Feb 25. 76(1): 148-160

[Regulatory mechanisms of mitochondrial dynamics and its emerging role in renal pathophysiology].

Zi-Xuan Tan, Wu-Zheng Zhu.

Mitochondria are dynamically changing organelles that maintain stable mitochondrial morphology, number, and function through constant fusion and division, a process known as mitochondrial dynamics, which is an important mechanism for mitochondrial quality control. Excessive fusion and division of mitochondria can lead to a homeostatic imbalance in mitochondrial dynamics, causing mitochondrial dysfunction, leading to cellular damage, and even death. The physiological functions of the kidney are mainly powered by mitochondria, and homeostatic imbalance in mitochondrial dynamics affects mitochondrial function and is closely related to renal diseases such as acute kidney injury and diabetic nephropathy. This article reviews the regulation of mitochondrial kinetics, how imbalances in mitochondrial kinetic homeostasis affect mitochondrial injury, and the impact of mitochondrial injury on renal pathophysiology, in order to improve understanding and knowledge of the role of mitochondria in renal disease.
Nat Commun. 2024 Mar 08. 15(1): 2142

Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.

Daniel M Virga, Stevie Hamilton, Bertha Osei, Abigail Morgan, Parker Kneis, Emiliano Zamponi, Natalie J Park, Victoria L Hewitt, David Zhang, Kevin C Gonzalez, Fiona M Russell, D Grahame Hardie, Julien Prudent, Erik Bloss, Attila Losonczy, Franck Polleux, Tommy L Lewis.

Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.

DOI: https://doi.org/10.1038/s41467-024-46463-w
J Zhejiang Univ Sci B. 2024 Mar 15. pii: 1673-1581(2024)03-0197-15. [Epub ahead of print]25(3): 197-211

Advances in the study of mitophagy in osteoarthritis.

Hong Cao, Xuchang Zhou, Bowen Xu, Han Hu, Jianming Guo, Miao Wang, Nan Li, Zou Jun.

  Osteoarthritis (OA), characterized by cartilage degeneration, synovial inflammation, and subchondral bone remodeling, is among the most common musculoskeletal disorders globally in people over 60 years of age. The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process. Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism. Therefore, maintaining mitochondrial homeostasis is an important strategy to mitigate OA. Mitophagy is a vital process for autophagosomes to target, engulf, and remove damaged and dysfunctional mitochondria, thereby maintaining mitochondrial homeostasis. Cumulative studies have revealed a strong association between mitophagy and OA, suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA. By reviewing the literature on mitophagy and OA published in recent years, this paper elaborates the potential mechanism of mitophagy regulating OA, thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.

Keywords:  Apoptosis; Chondrocyte; Mitochondria; Mitophagy; Osteoarthritis

DOI:  https://doi.org/10.1631/jzus.B2300402
Biomaterials. 2024 Feb 26. pii: S0142-9612(24)00046-2. [Epub ahead of print]307 122512

Cuproptotic nanoinducer-driven proteotoxic stress potentiates cancer immunotherapy by activating the mtDNA-cGAS-STING signaling.

Xinying Yu, Bei Li, Jie Yan, Wenxi Li, Hao Tian, Guohao Wang, Songtao Zhou, Yunlu Dai.

  Proteotoxic stress, caused by the accumulation of abnormal unfolded or misfolded cellular proteins, can efficiently activate inflammatory innate immune response. Initiating the mitochondrial proteotoxic stress might go forward to enable the cytosolic release of intramitochondrial DNA (mtDNA) for the immune-related mtDNA-cGAS-STING activation, which however is easily eliminated by a cell self-protection, i.e., mitophagy. In light of this, a nanoinducer (PCM) is reported to trigger mitophagy-inhibited cuproptotic proteotoxicity. Through a simple metal-phenolic coordination, PCMs reduce the original Cu2+ with the phenolic group of PEG-polyphenol-chlorin e6 (Ce6) into Cu+. Cu+ thereby performs its high binding affinity to dihydrolipoamide S-acetyltransferase (DLAT) and aggregates DLAT for cuproptotic proteotoxic stress and mitochondrial respiratory inhibition. Meanwhile, intracellular oxygen saved from the respiratory failure can be utilized by PCM-conjugated Ce6 to boost the proteotoxic stress. Next, PCM-loaded mitophagy inhibitor (Mdivi-1) protects proteotoxic products from being mitophagy-eliminated, which allows more mtDNA to be released in the cytosol and successfully stimulate the cGAS-STING signaling. In vitro and in vivo studies reveal that PCMs can upregulate the tumor-infiltrated NK cells by 24% and enhance the cytotoxic killing of effector T cells. This study proposes an anti-tumor immunotherapy through mitochondrial proteotoxicity.

Keywords:  Cu(+); Cuproptosis; Metal-phenolic coordination; mitophagy inhibition; mtDNA–cGAS–STING pathway; proteotoxic stress

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122512
Mol Ther. 2024 Mar 06. pii: S1525-0016(24)00144-8. [Epub ahead of print]

C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis.

Baokui Ye, Binfeng Chen, Chaohuan Guo, Ningjing Xiong, Yuefang Huang, Mengyuan Li, Yimei Lai, Jin Li, Mianjing Zhou, Shuang Wang, Shuyi Wang, Niansheng Yang, Hui Zhang.

  Podocytes are essential to maintaining the integrity of the glomerular filtration barrier, yet they are frequently affected in lupus nephritis (LN). Here, we show that the significant upregulation of Drp1S616 phosphorylation in podocytes promotes mitochondrial fission, leading to mitochondrial dysfunction and podocyte injury in LN. Inhibition or knockdown of Drp1 promotes mitochondrial fusion and protects podocytes from injury induced by LN serum. In vivo, pharmacological inhibition of Drp1 reduces the phosphorylation of Drp1S616 in podocytes in lupus-prone mice. Podocyte injury is reversed when Drp1 is inhibited, resulting in the alleviation of proteinuria. Mechanistically, complement component C5a (C5a) upregulates the phosphorylation of Drp1S616 and promotes mitochondrial fission in podocytes. Moreover, the expression of C5a receptor 1 (C5aR1) is notably upregulated in podocytes in LN. C5a-C5aR1 axis-controlled phosphorylation of Drp1S616 and mitochondrial fission are substantially suppressed when C5aR1 is knocked down by siRNA. Moreover, lupus-prone mice treated with C5aR inhibitor show reduced phosphorylation of Drp1S616 in podocytes, resulting in significantly less podocyte damage. Together, this study uncovers a novel mechanism by which the C5a-C5aR1 axis promotes podocyte injury by enhancing Drp1-mediated mitochondrial fission, which could have significant implications for the treatment of LN.

Keywords:  C5a-C5aR1 axis; Drp1; lupus nephritis; mitochondrial fission; podocyte injury

DOI:  https://doi.org/10.1016/j.ymthe.2024.03.003
Curr Med Chem. 2024 Mar 01.

Defective Mitophagy Impairs Response to Inflammatory Activation of Macrophage-Like Cells.

Alexander N Orekhov, Alexander D Zhuravlev, Andrey Y Vinokurov, Nikita G Nikiforov, Andrey V Omelchenko, Vasily N Sukhorukov, Vasily V Sinyov, Igor A Sobenin.

  BACKGROUND AND AIMS: The role of mitophagy in atherosclerosis has been extensively studied during the last few years. It was shown that mitophagy is involved in the regulation of macrophages, which are important players as immune cells in atherosclerosis development. In this study, we investigated the relationship between mitophagy and response to inflammatory stimulation of macrophage-like cells. Six cybrid cell lines with normal mitophagy, that is, increasing in response to stimulation, and 7 lines with defective mitophagy not responding to stimulation were obtained. The objective of the study was to compare the nature of the inflammatory response in normal and defective mitophagy in order to elucidate the role of mitophagy defects in inflammation.METHODS: We used cytoplasmic hybrids (cybrids) as cellular models, created using mitochondrial DNA from different atherosclerosis patients. Mitophagy was stimulated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and assessed as the degree of colocalization of mitochondria with lysosomes using confocal microscopy. Western blotting methods were used for the determination of proteins involved in the exact mechanism of mitophagy. Experiments with stimulation of mitophagy show a high correlation between these two approaches (microscopy and blotting). The pro-inflammatory response of cybrids was stimulated with bacterial lipopolysaccharide (LPS). The extent of the inflammatory response was assessed by the secretion of cytokines CCL2, IL8, IL6, IL1β, and TNF measured by ELISA.
RESULTS: Basal level of secretion of cytokines CCL2, IL8 and TNF was 1.5-2 times higher in cultures of cybrids with defective mitophagy compared to cells with normal mitophagy. This suggests a persistently elevated inflammatory response in cells with defective mitophagy, even in the absence of an inflammatory stimulus. Such cells in the tissue will constantly recruit other immune cells, which is characteristic of macrophages derived from monocytes circulating in the blood of patients with atherosclerosis. We observed significant differences in the degree and type of response to inflammatory activation in cybrids with defective mitophagy. These differences were not so much quantitative as they were dramatically qualitative. Compared with cells with normal mitophagy, in cells with defective mitophagy, the relative (to basal) secretion of IL8, IL6 and IL1b increased after the second LPS activation. This indicates a possible lack of tolerance to inflammatory activation in cells with defective mitophagy, since typically, re-activation reveals a smaller pro-inflammatory cytokine response, allowing the inflammatory process to resolve. In cells with normal mitophagy, exactly this normal (tolerant) inflammatory reaction was observed.
CONCLUSION: Data on the involvement of mitophagy, including defective mitophagy, in disturbances of the inflammatory response in sepsis, viral infections, autoimmune diseases and other pathologies have previously been reported. In this work, we studied the role of defective mitophagy in non-infectious chronic inflammatory diseases using the example of atherosclerosis. We showed a dramatic disruption of the inflammatory response associated with defective mitophagy. Compared with cybrids with normal mitophagy, in cybrids with defective mitophagy, the secretion of all studied cytokines changed significantly both quantitatively and qualitatively. In particular, the secretion of 3 of 5 cytokines demonstrated an intolerant inflammatory response manifested by increased secretion after repeated inflammatory stimulation. Such an intolerant reaction likely indicates a significant disruption of the pro-inflammatory response of macrophages, which can contribute to the chronification of inflammation. Elucidating the mechanisms of chronification of inflammation is extremely important for the search for fundamentally new pharmacological targets and the development of drugs for the prevention and treatment of chronic inflammatory diseases, including atherosclerosis and diseases characteristic of inflammation. Such diseases account for up to 80% of morbidity and mortality.

Keywords:  Mitochondria; atherosclerosis; chronification of inflammation.; cybrids; cytokines; defective mitophagy

DOI:  https://doi.org/10.2174/0109298673294643240228105957
Cell Mol Biol Lett. 2024 Mar 04. 29(1): 31

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury.

Zhixia Song, Yao Xia, Lang Shi, Hongchu Zha, Jing Huang, Xiaohong Xiang, Huiming Li, Hua Huang, Ruchi Yue, Hongtao Wang, Jiefu Zhu.

  BACKGROUND: Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI.METHODS: We induced ischemia-reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy.
RESULTS: Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice.
CONCLUSIONS: Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.

Keywords:  Acute kidney injury; Drp1; Fis1; Ischemia reperfusion injury; Mitochondria

DOI:  https://doi.org/10.1186/s11658-024-00553-1
Biomater Res. 2024 ;28 0006

CD62E- and ROS-Responsive ETS Improves Cartilage Repair by Inhibiting Endothelial Cell Activation through OPA1-Mediated Mitochondrial Homeostasis.

Pengcheng Tu, Yalan Pan, Lining Wang, Bin Li, Xiaoxian Sun, Zhongqing Liang, Mengmin Liu, Zitong Zhao, Chengjie Wu, Jianwei Wang, Zhifang Wang, Yu Song, Yafeng Zhang, Yong Ma, Yang Guo.

Background: In the environment of cartilage injury, the activation of vascular endothelial cell (VEC), marked with excessive CD62E and reactive oxygen species (ROS), can affect the formation of hyaluronic cartilage. Therefore, we developed a CD62E- and ROS-responsive drug delivery system using E-selectin binding peptide, Thioketal, and silk fibroin (ETS) to achieve targeted delivery and controlled release of Clematis triterpenoid saponins (CS) against activated VEC, and thus promote cartilage regeneration. Methods: We prepared and characterized ETS/CS and verified their CD62E- and ROS-responsive properties in vitro. We investigated the effect and underlying mechanism of ETS/CS on inhibiting VEC activation and promoting chondrogenic differentiation of bone marrow stromal cells (BMSCs). We also analyzed the effect of ETS/CS on suppressing the activated VEC-macrophage inflammatory cascade in vitro. Additionally, we constructed a rat knee cartilage defect model and administered ETS/CS combined with BMSC-containing hydrogels. We detected the cartilage differentiation, the level of VEC activation and macrophage in the new tissue, and synovial tissue. Results: ETS/CS was able to interact with VEC and inhibit VEC activation through the carried CS. Coculture experiments verified ETS/CS promoted chondrogenic differentiation of BMSCs by inhibiting the activated VEC-induced inflammatory cascade of macrophages via OPA1-mediated mitochondrial homeostasis. In the rat knee cartilage defect model, ETS/CS reduced VEC activation, migration, angiogenesis in new tissues, inhibited macrophage infiltration and inflammation, promoted chondrogenic differentiation of BMSCs in the defective areas. Conclusions: CD62E- and ROS-responsive ETS/CS promoted cartilage repair by inhibiting VEC activation and macrophage inflammation and promoting BMSC chondrogenesis. Therefore, it is a promising therapeutic strategy to promote articular cartilage repair.

DOI: https://doi.org/10.34133/bmr.0006
Cell Biochem Biophys. 2024 Mar 04.

Drp1: Focus on Diseases Triggered by the Mitochondrial Pathway.

Fulin Sun, Min Fang, Huhu Zhang, Qinghang Song, Shuang Li, Ya Li, Shuyao Jiang, Lina Yang.

  Drp1 (Dynamin-Related Protein 1) is a cytoplasmic GTPase protein encoded by the DNM1L gene that influences mitochondrial dynamics by mediating mitochondrial fission processes. Drp1 has been demonstrated to play an important role in a variety of life activities such as cell survival, proliferation, migration, and death. Drp1 has been shown to play different physiological roles under different physiological conditions, such as normal and inflammation. Recently studies have revealed that Drp1 plays a critical role in the occurrence, development, and aggravation of a series of diseases, thereby it serves as a potential therapeutic target for them. In this paper, we review the structure and biological properties of Drp1, summarize the biological processes that occur in the inflammatory response to Drp1, discuss its role in various cancers triggered by the mitochondrial pathway and investigate effective methods for targeting Drp1 in cancer treatment. We also synthesized the phenomena of Drp1 involving in the triggering of other diseases. The results discussed herein contribute to our deeper understanding of mitochondrial kinetic pathway-induced diseases and their therapeutic applications. It is critical for advancing the understanding of the mechanisms of Drp1-induced mitochondrial diseases and preventive therapies.

Keywords:  Alzheimer’s disease; Cancer; Dynamin-Related Protein 1; Inflammation response; Mitochondrial dynamics; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12013-024-01245-5
Autophagy. 2024 Mar 08. 1-2

Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases.

Zhangyuan Yin, Daniel J Klionsky.

  The selective clearance of unwanted, damaged or dangerous components by macroautophagy/autophagy is critical for maintaining cellular homeostasis in organisms from yeast to humans. In recent years, significant progress has been made in understanding how phagophores selectively sequester specific cargo. Nevertheless, a fundamental question remains: Can distinct selective autophagy programs simultaneously operate within the same cell? A recent study from the Baehrecke lab has unveiled a developmentally programmed Pink1-dependent reticulophagy process in the Drosophila intestine. Furthermore, this study demonstrated that autophagy differentially clears mitochondria and ER in the same cell under the regulation of Pink1 through different E3 ubiquitin ligases, highlighting the need for further exploration in understanding the complexity of autophagic substrate selection and crosstalk between diverse autophagy programs.

Keywords:  Autophagy receptor; Keap1; Pink1; mitophagy; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2024.2323294
Nat Commun. 2024 Mar 04. 15(1): 1965

NDUFS4 regulates cristae remodeling in diabetic kidney disease.

Koki Mise, Jianyin Long, Daniel L Galvan, Zengchun Ye, Guizhen Fan, Rajesh Sharma, Irina I Serysheva, Travis I Moore, Collene R Jeter, M Anna Zal, Motoo Araki, Jun Wada, Paul T Schumacker, Benny H Chang, Farhad R Danesh.

The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.

DOI: https://doi.org/10.1038/s41467-024-46366-w
Mod Rheumatol. 2024 Mar 05. pii: roae015. [Epub ahead of print]

LncRNA OIP5-AS1 promotes mitophagy to alleviate osteoarthritis by up-regulating PPAR-γ to activate AMPK/Akt/mTOR pathway.

Zhilu Sun, Jie Tang, Ting You, Bihong Zhang, Yu Liu, Jing Liu.

  BACKGROUND: Osteoarthritis (OA) is the most common chronic joint degenerative disease. Mitophagy is closely related to OA pathogenesis. Herein, we investigated the role of lncRNA OIP5-AS1 in regulating mitophagy during OA.METHODS: RT-qPCR and Western blotting were utilized to analyze gene and protein levels. RIP and RNA pull down verified the relationship between OIP5-AS1, FUS and PPAR-γ. CCK-8 assay detected cells viability. ELISA evaluated the secretion of inflammatory cytokines. Flow cytometry measured the contents of ROS and Ca2+. Immunofluorescence staining analyzed TOMM20 and LC3B levels. JC-1 staining was adopted to measure mitochondrial membrane potential. The changes of mitophagy were analyzed by TEM.
RESULTS: LPS treatment contributed to the decrease of chondrocytes viability, calcium level and inhibited mitochondrial membrane potential, while elevated the secretion of inflammatory factors, ROS accumulation and TOMM20 expression. Additionally, LPS decreased the ratio of LC3II/I, Parkin and PINK1 protein levels, and increased p62 and TOMM20 protein levels. Furthermore, overexpression of OIP5-AS1 inhibited LPS-induced chondrocytes injury and activated mitophagy. OIP5-AS1 upregulated PPAR-γ mRNA level to regulate AMPK/Akt/mTOR signaling by interacting with FUS. In addition, PPAR-γ overexpression alleviated LPS induced chondrocytes injury by activating AMPK/Akt/mTOR signaling. Knockdown of PPAR-γ reversed the promotion of OIP5-AS1 upregulation on mitophagy.
CONCLUSION: OIP5-AS1 promotes PPAR-γ expression to activate the AMPK/Akt/mTOR signaling, thereby enhancing mitophagy and alleviating OA progression. It is suggested that OIP5-AS1 may function as a protector in OA development.

Keywords:  OIP5-AS1; PPAR-γ; mitophagy; osteoarthritis

DOI:  https://doi.org/10.1093/mr/roae015
Sci Rep. 2024 Mar 08. 14(1): 5754

Apigenin ameliorates genitourinary dysfunction in a type 1 diabetic rat model via Drp1 modulation.

Mai Khaled, Raghda A M Salama, Azza Aboughalia, Mai Tarek, Nesma Mohamed Fawzy.

  The present study aimed to explore the potential ameliorative effect of apigenin (APG) against diabetes-associated genitourinary complications in rats. A diabetic rat model was induced by the intraperitoneal injection of streptozotocin (STZ). All experimental animals were treated with vehicle or vehicle plus APG at a dose of 0.78 mg/kg/day for 10 days, either once diabetes was confirmed or at the end of the 3rd week after confirmation of diabetes. Rats were sacrificed at the end of the fifth week. In addition to the histological assessment, an analysis of kidney function tests and serum testosterone was performed to assess diabetic genitourinary complications. Gene expression of the mitochondrial fission protein, dynamin related protein 1 (Drp1), was measured in renal and testicular tissues using qRT PCR. APG can increase body weight, reduce blood glucose levels, and improve renal and testicular functions in diabetic rats. APG decreased Drp1 overexpression in diabetic animals' kidneys and testes. In summary, our current work discloses that APG attenuates diabetic genitourinary lesions in rats via suppressing Drp1 overexpression.

Keywords:  Apigenin; Diabetes mellitus; Diabetic nephropathy; Dynamin-related protein 1; Genitourinary complications

DOI:  https://doi.org/10.1038/s41598-024-56395-6
Mol Med Rep. 2024 May;pii: 68. [Epub ahead of print]29(5):

[Retracted] Liraglutide repairs the infarcted heart: The role of the SIRT1/Parkin/mitophagy pathway.

Huiying Qiao, Haiyan Ren, He Du, Minfang Zhang, Xiaofang Xiong, Rong Lv.

  Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the immunofluorescence data shown in Fig. 2G, the mitochondria‑ and lysosome‑stained images in Fig. 3C, the JC‑1 staining images in Fig. 4C and the immunofluorescence data in Fig. 5G were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to Molecular Medicine Reports, or were under consideration for publication at around the same time. In view of the fact that certain of the abovementioned data had already apparently been published previously, the Editor of Molecular Medicine Reports has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 3722‑3734, 2018; DOI: 10.3892/mmr.2018.8371].

Keywords:  NAD-dependent protein deacetylase sirtuin-1; Parkin; apoptosis; infarcted heart; liraglutide; mitochondria; mitophagy

DOI:  https://doi.org/10.3892/mmr.2024.13192
Cancer Sci. 2024 Mar 03.

Mitochondrial fission enhances IL-6-induced metastatic potential in ovarian cancer via ERK1/2 activation.

Juwon Lee, Youngjin Han, Soochi Kim, HyunA Jo, Wenyu Wang, Untack Cho, Se Ik Kim, Boyun Kim, Yong Sang Song.

  Ovarian cancer is a lethal gynecologic cancer mostly diagnosed in an advanced stage with an accumulation of ascites. Interleukin-6 (IL-6), a pro-inflammatory cytokine is highly elevated in malignant ascites and plays a pleiotropic role in cancer progression. Mitochondria are dynamic organelles that undergo fission and fusion in response to external stimuli and dysregulation in their dynamics has been implicated in cancer progression and metastasis. Here, we investigate the effect of IL-6 on mitochondrial dynamics in ovarian cancer cells (OVCs) and its impact on metastatic potential. Treatment with IL-6 on ovarian cancer cell lines (SKOV3 and PA-1) led to an elevation in the metastatic potential of OVCs. Interestingly, a positive association was observed between dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, and IL-6R in metastatic ovarian cancer tissues. Additionally, IL-6 treatment on OVCs was linked to the activation of Drp1, with a notable increase in the ratio of the inhibitory form p-Drp1(S637) to the active form p-Drp1(S616), indicating enhanced mitochondrial fission. Moreover, IL-6 treatment triggered the activation of ERK1/2, and inhibiting ERK1/2 mitigated IL-6-induced mitochondrial fission. Suppressing mitochondrial fission through siRNA transfection and a pharmacological inhibitor reduced the IL-6-induced migration and invasion of OVCs. This was further supported by 3D invasion assays using patient-derived spheroids. Altogether, our study suggests the role of mitochondrial fission in the metastatic potential of OVCs induced by IL-6. The inhibition of mitochondrial fission could be a potential therapeutic approach to suppress the metastasis of ovarian cancer.

Keywords:  Drp13; IL-62; metastasis5; mitochondria1; ovarian cancer4

DOI:  https://doi.org/10.1111/cas.16064