bims-tofagi 2023-10-29 papers

on Mitophagy

Issue of 2023‒10‒29
seventeen papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.
Mitophagy in Astrocytes Is Required for the Health of Optic Nerve.
The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.
Editorial: Mitochondrial control of cell fate.
Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer.
Ceramides and their roles in programmed cell death.
Unveiling mitophagy-mediated molecular heterogeneity and development of a risk signature model for colorectal cancer by integrated scRNA-seq and bulk RNA-seq analysis.
A molecular simulation study of the clinical G409V mutant in PINK1 associated with early-onset Parkinson's disease.
Kaempferol Alleviates Mitochondrial Damage by Reducing Mitochondrial Reactive Oxygen Species Production in Lipopolysaccharide-Induced Prostate Organoids.
Lasmiditan restores mitochondrial quality control mechanisms and accelerates renal recovery after ischemia-reperfusion injury.
Polystyrene nanoparticles induced mammalian intestine damage caused by blockage of BNIP3/NIX-mediated mitophagy and gut microbiota alteration.
Targeting mitophagy for depression amelioration: a novel therapeutic strategy.
Autophagy in Parkinson's Disease.
Mitochondrial Dysfunction in Dopaminergic Neurons Derived from Patients with LRRK2- and SNCA-Associated Genetic Forms of Parkinson's Disease.
Baicalin mitigates nephropathogenic infectious bronchitis virus infection-induced spleen injury via modulation of mitophagy and macrophage polarization in Hy-Line chick.
Impaired Autophagic Flux in Glucose-Deprived Cells: An Outcome of Lysosomal Acidification Failure Exacerbated by Mitophagy Dysfunction.
Parkin Promotes Airway Inflammatory Response to Interferon Gamma.

Autophagy. 2023 Oct 24.

Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.

Kun Gao, Yingji Chen, Ren Mo, Chenji Wang.

  Mitophagy, the process of removing damaged mitochondria to promote cell survival, plays a crucial role in cellular functionality. However, excessive, or uncontrolled mitophagy can lead to reduced mitochondrial content that burdens the remaining organelles, triggering mitophagy-mediated cell death. FBXL4 mutations, which affect the substrate-binding adaptor of the CUL1 (cullin 1)-RING ubiquitin ligase complex (CRL1), have been linked to mitochondrial DNA depletion syndrome type 13 (MTDPS13) characterized by reduced mtDNA content and impaired energy production in affected organs. However, the mechanism behind FBXL4 mutation-driven MTDPS13 remain poorly understood. In a recent study, we demonstrate that the CRL1-FBXL4 complex promotes the degradation of BNIP3 and BNIP3L, two key mitophagy cargo receptors. Deficiency of FBXL4 results in a strong accumulation of BNIP3 and BNIP3L proteins and triggers high levels of BNIP3- and BNIP3L-dependent mitophagy. Patient-derived FBXL4 mutations do not affect its interaction with BNIP3 and BNIP3L but impair the assembly of an active CRL1-FBXL4 complex. Furthermore, excessive mitophagy is observed in knockin mice carrying a patient-derived FBXL4 mutation, and in cortical neurons generated from human patient induced pluripotent stem cells (hiPSCs). These findings support the model that the CRL1-FBXL4 complex tightly restricts basal mitophagy, and its dysregulation leads to severe symptoms of MTDPS13.

Keywords:  Lysosome; mitochondria; mitophagy; multi-system disorder; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2023.2274260
Cells. 2023 Oct 20. pii: 2496. [Epub ahead of print]12(20):

Mitophagy in Astrocytes Is Required for the Health of Optic Nerve.

Meysam Yazdankhah, Sayan Ghosh, Haitao Liu, Stacey Hose, J Samuel Zigler, Debasish Sinha.

  Mitochondrial dysfunction in astrocytes has been implicated in the development of various neurological disorders. Mitophagy, mitochondrial autophagy, is required for proper mitochondrial function by preventing the accumulation of damaged mitochondria. The importance of mitophagy, specifically in the astrocytes of the optic nerve (ON), has been little studied. We introduce an animal model in which two separate mutations act synergistically to produce severe ON degeneration. The first mutation is in Cryba1, which encodes βA3/A1-crystallin, a lens protein also expressed in astrocytes, where it regulates lysosomal pH. The second mutation is in Bckdk, which encodes branched-chain ketoacid dehydrogenase kinase, which is ubiquitously expressed in the mitochondrial matrix and involved in the catabolism of the branched-chain amino acids. BCKDK is essential for mitochondrial function and the amelioration of oxidative stress. Neither of the mutations in isolation has a significant effect on the ON, but animals homozygous for both mutations (DM) exhibit very serious ON degeneration. ON astrocytes from these double-mutant (DM) animals have lysosomal defects, including impaired mitophagy, and dysfunctional mitochondria. Urolithin A can rescue the mitophagy impairment in DM astrocytes and reduce ON degeneration. These data demonstrate that efficient mitophagy in astrocytes is required for ON health and functional integrity.

Keywords:  BCKDK; astrocytes; autophagy; lysosome; mitochondria; mitophagy; optic nerve; βA3/A1-crystallin

DOI:  https://doi.org/10.3390/cells12202496
Autophagy. 2023 Oct 24.

The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.

Yu Song, Huaizhen Liang, Gaocai Li, Liang Ma, Dingchao Zhu, Weifeng Zhang, Bide Tong, Shuai Li, Yong Gao, Xinghuo Wu, Yukun Zhang, Xiaobo Feng, Kun Wang, Cao Yang.

  Intervertebral disc degeneration (IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and intervertebral disc integrity benefits largely from well-controlled mitochondrial quality, surveilled by mitochondrial dynamics (fission and fusion) and mitophagy, but the outcome is cellular context-dependent that remain to be clarified. Our studies revealed that the loss of NLRX1 is correlated with NP cell senescence and IDD progression, which involve disordered mitochondrial quality. Further using animal and in vitro tissue and cell models, we demonstrated that NLRX1 could facilitate mitochondrial quality by coupling mitochondrial dynamic factors (p-DNM1L, L-OPA1:S-OPA1, OMA1) and mitophagy activity. Conversely, mitochondrial collapse occurred in NLRX1-defective NP cells and switched on the compensatory PINK1-PRKN pathway that led to excessive mitophagy and aggressive NP cell senescence. Mechanistically, NLRX1 was originally shown to interact with zinc transporter SLC39A7 and modulate mitochondrial Zn2+ trafficking via the formation of an NLRX1-SLC39A7 complex on the mitochondrial membrane of NP cells, subsequently orchestrating mitochondrial dynamics and mitophagy. The restoration of NLRX1 function by gene overexpression or pharmacological agonist (NX-13) treatment showed great potential for regulating mitochondrial fission with synchronous fusion and mitophagy, thus sustaining mitochondrial homeostasis, ameliorating NP cell senescence and rejuvenating intervertebral discs. Collectively, our findings highlight a working model whereby the NLRX1-SLC39A7 complex coupled mitochondrial dynamics and mitophagy activity to surveil and target damaged mitochondria for degradation, which determines the beneficial function of the mitochondrial surveillance system and ultimately rejuvenates intervertebral discs.

Keywords:  Intervertebral disc degeneration; NLRX1; SLC39A7; mitochondrial dynamics; mitophagy; nucleus pulposus

DOI:  https://doi.org/10.1080/15548627.2023.2274205
Front Cell Dev Biol. 2023 ;11 1302075

Editorial: Mitochondrial control of cell fate.

Guohua Gong, Huiliang Zhang, Stephen C Kolwicz.



Keywords:  cell fate; dynamics; homeostasis; mitochondrial biogenesis; mitophagy

DOI:  https://doi.org/10.3389/fcell.2023.1302075
Clin Transl Med. 2023 Oct;13(10): e1457

Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer.

Xin Sun, Guiqin Ye, Jiuzhou Li, Huafeng Shou, Gongxun Bai, Jianbin Zhang.

  BACKGROUND: Insulin-like growth Factor 2 mRNA-binding protein 3 (IGF2BP3) is a highly conserved RNA-binding protein and plays a critical role in regulating posttranscriptional modifications.METHODS: Immunoprecipitation was used to examine the interaction of Parkin and IGF2BP3. Mass spectrometry was performed to identify the ubiquitination sites of IGF2BP3. RNA-immunoprecipitation was conducted to examine the target genes of IGF2BP3. Xenograft mouse model was constructed to determine the tumorigenesis of IGF2BP3.
RESULTS: IGF2BP3 expression is negatively correlated with Parkin expression in human cervical cancer cells and tissues. Parkin directly interacts with IGF2BP3, and overexpression of Parkin causes the proteasomal degradation of IGF2BP3, while knockdown of PARK2 increases the protein levels of IGF2BP3. Mechanistically, in vivo and in vitro ubiquitination assays demonstrated that Parkin is able to ubiquitinate IGF2BP3. Moreover, the ubiquitination site of IGF2BP3 was identified at K213 in the first KH domain of IGF2BP3. IGF2BP3 mutation results in the loss of its oncogenic function as an m6A reader, resulting in the inactivation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, IGF2BP3 mutation results in the attenuation of Parkin-mediated mitophagy, indicating its inverse role in regulating Parkin. Consequently, the tumourigenesis of cervical cancer is also inhibited by IGF2BP3 mutation.
CONCLUSION: IGF2BP3 is ubiquitinated and regulated by the E3 ubiquitin ligase Parkin in human cervical cancer and ubiquitination modification plays an important role in modulating IGF2BP3 function. Thus, understanding the role of IGF2BP3 in tumourigenesis could provide new insights into cervical cancer therapy.

Keywords:  IGF2BP3; cervical cancer; mitophagy; parkin; ubiquitination

DOI:  https://doi.org/10.1002/ctm2.1457
Adv Med Sci. 2023 Oct 20. pii: S1896-1126(23)00044-5. [Epub ahead of print]68(2): 417-425

Ceramides and their roles in programmed cell death.

Martina Bago Pilátová, Zuzana Solárová, Roman Mezencev, Peter Solár.

  Programmed cell death plays a crucial role in maintaining the homeostasis and integrity of multicellular organisms, and its dysregulation contributes to the pathogenesis of many diseases. Programmed cell death is regulated by a range of macromolecules and low-molecular messengers, including ceramides. Endogenous ceramides have different functions, that are influenced by their localization and the presence of their target molecules. This article provides an overview of the current understanding of ceramides and their impact on various types of programmed cell death, including apoptosis, anoikis, macroautophagy and mitophagy, and necroptosis. Moreover, it highlights the emergence of dihydroceramides as a new class of bioactive sphingolipids and their downstream targets as well as their future roles in cancer cell growth, drug resistance and tumor metastasis.

Keywords:  Anoikis; Apoptosis; Autophagy; Ceramide; Mitophagy; Necroptosis

DOI:  https://doi.org/10.1016/j.advms.2023.10.004
Gastroenterol Rep (Oxf). 2023 ;11 goad066

Unveiling mitophagy-mediated molecular heterogeneity and development of a risk signature model for colorectal cancer by integrated scRNA-seq and bulk RNA-seq analysis.

Han Gao, Qi Zou, Linyun Ma, Keyu Cai, Yi Sun, Li Lu, Donglin Ren, Bang Hu.

  Background: Accumulating researchers have recognized mitophagy as a key player in tumors, but few studies have investigated its role in the tumor microenvironment (TME). Advances in the technology of single-cell RNA sequencing (scRNA-seq) have allowed unveiling the concealed features of the TME at cellular resolution. This study aimed to elucidate the role of mitophagy within the TME of colorectal cancer (CRC) and to establish a mitophagy-mediated risk model.Methods: We assessed mitophagy-related pathway activities at both single-cell and tissue levels. Subsequently, an unsupervised clustering algorithm was employed to identify mitophagy-mediated subtypes. Furthermore, we developed a mitophagy-mediated risk signature (MMRS) using least absolute shrinkage and selection operator (LASSO) Cox analysis and constructed a MMRS model incorporating the risk score and clinical variables. Subsequently, we used quantitative reverse transcription polymerase chain reaction analysis to verify the expression of the screened genes.
Results: We retrieved and annotated a total of 14,719 cells from eight samples in the scRNA-seq GSE132465 data set. The activities of mitophagy-related pathways were uniformly upregulated in cancer cells. Integrating with bulk RNA-seq data, we identified two mitophagy-mediated clusters (C1 and C2) with distinct characteristics and prognoses. C2 was identified as a mitophagy-high cluster. Then, we developed a five-gene MMRS via LASSO Cox analysis in The Cancer Genome Atlas (TCGA) cohort. We utilized the GSE39582 cohort to validate the efficacy of our model. The expression of CX3CL1 and INHBB was upregulated in CRC tissues.
Conclusions: The present study identified two mitophagy-mediated CRC subtypes with distinct features. Our MMRS may provide potential therapeutic strategies for CRC. The findings of our work offer novel insights into the involvement of mitophagy in CRC.

Keywords:  anticancer therapy; colorectal cancer; mitophagy; risk signature; scRNA-seq

DOI:  https://doi.org/10.1093/gastro/goad066
Int J Biol Macromol. 2023 Oct 19. pii: S0141-8130(23)04463-X. [Epub ahead of print] 127566

A molecular simulation study of the clinical G409V mutant in PINK1 associated with early-onset Parkinson's disease.

Hsuan-Hsuan Lo, Ya-Jyun Chen, Cheng-Han Jiang, Chih-Hua Tseng, Chia-Ning Yang.

  The serine/threonine kinase PINK1 is responsible for phosphorylating a ubiquitin (Ub)-like domain in an E3 Ub ligase Parkin protein and a Parkin-bound Ub. PINK1 works as a mitochondrial quality control by phosphorylating and activating the E3 ubiquitin ligase Parkin. Recent medicinal study has reported that mutations of Parkin and PINK1 cause defects in mitophagy and induce early-onset Parkinson's disease (EOPD). In this study, we conducted molecular dynamics simulations to investigate the structural discrepancy caused by a clinical G409V mutation in PINK1 kinase domain's A-loop. The Ub phosphorylation begins with PINK1 D362 deprotonating the hydroxyl group of the substrate Ub's S65' and PINK1's A-loop is responsible for coordinating S65'. On contrary to G409 offering structural plasticity, the replaced, bulky V409 interferes with the alignment of D362-S65', seriously hampering Ub phosphorylation, leading to the accumulation of damaged mitochondria, and ultimately EOPD. In this study, we predicted the hPINK1WT-UbWT binding mode and detected the structural impact brought by G409V replacement. It is expected the concluded remarks to be beneficial for developing cures to alleviate structural interference and restore PINK1 function.

Keywords:  Early-onset Parkinson's disease; Molecular dynamics simulations; PINK1

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127566
Foods. 2023 Oct 20. pii: 3836. [Epub ahead of print]12(20):

Kaempferol Alleviates Mitochondrial Damage by Reducing Mitochondrial Reactive Oxygen Species Production in Lipopolysaccharide-Induced Prostate Organoids.

Myeong Joon Lee, Yeonoh Cho, Yujin Hwang, Youngheun Jo, Yeon-Gu Kim, Seung Hwan Lee, Jong Hun Lee.

  Common prostate diseases such as prostatitis and benign prostatic hyperplasia (BPH) have a high incidence at any age. Cellular stresses, such as reactive oxygen species (ROS) and chronic inflammation, are implicated in prostate enlargement and cancer progression and development. Kaempferol is a flavonoid found in abundance in various plants, including broccoli and spinach, and has been reported to exhibit positive biological activities, such as antioxidant and anti-inflammatory properties. In the present study, we introduced prostate organoids to investigate the protective effects of kaempferol against various cellular stresses. The levels of COX-2, iNOS, p-IκB, a pro-inflammatory cytokine, and ROS were increased by LPS treatment but reversed by kaempferol treatment. Kaempferol activated the nuclear factor erythroid 2-related factor 2(Nrf2)-related pathway and enhanced the mitochondrial quality control proteins PGC-1α, PINK1, Parkin, and Beclin. The increase in mitochondrial ROS and oxygen consumption induced by LPS was stabilized by kaempferol treatment. First, our study used prostate organoids as a novel evaluation platform. Secondly, it was demonstrated that kaempferol could alleviate the mitochondrial damage in LPS-induced induced prostate organoids by reducing the production of mitochondrial ROS.

Keywords:  ROS; anti-inflammation; antioxidant; kaempferol; mitochondrial homeostasis; mitophagy; organoid

DOI:  https://doi.org/10.3390/foods12203836
Biochem Pharmacol. 2023 Oct 21. pii: S0006-2952(23)00446-X. [Epub ahead of print]218 115855

Lasmiditan restores mitochondrial quality control mechanisms and accelerates renal recovery after ischemia-reperfusion injury.

Kevin A Hurtado, Jaroslav Janda, Rick G Schnellmann.

  BACKGROUND: Mitochondrial dysfunction is a well-established result of acute kidney injury (AKI). Previously, we identified that 5-hydroxytryptamine 1F (5-HT1F) receptor agonism with lasmiditan induces mitochondrial biogenesis (MB) and improves renal vasculature and function in an AKI mouse model. We hypothesize that lasmiditan also modulates mitochondrial dynamics and mitophagy in a mouse model of AKI.METHODS: Male mice were subjected to renal ischemia/reperfusion (I/R) and treated daily with lasmiditan (0.3 mg/kg) or vehicle beginning 24 h after injury for 3 or 6d. Serum creatinine was measured to estimate glomerular filtration. Electron microscopy was used to assess mitochondrial morphology and mitophagy. Mitochondrial-related protein were confirmed with immunoblotting. Mitochondrial function was assessed with ATP measurements.
RESULTS: Lasmiditan treatment improved mitochondrial and kidney recovery as early as 3d post-AKI, as evidenced by increased ATP, and decreased serum creatinine, respectively. Electron micrographs of renal cortices revealed that lasmiditan also decreased mitochondrial damage and increased mitochondrial area and size by 6d after I/R injury. Additionally, lasmiditan treatment increased mitolysosomes by 3d, indicating induction of mitophagy. Phosphorylation of mitophagy-related proteins were also increased in the renal cortices of lasmiditan-treated AKI mice 3d after I/R injury, whereas fusion-related proteins were increased at 6d after I/R injury.
CONCLUSION: These data reveal that lasmiditan accelerates renal recovery, restores normal mitochondrial membrane and cristae morphology, decreases excessive mitochondrial fission, and accelerates mitophagy post-AKI in a time-dependent manner, establishing mitochondrial function and recovery from AKI.

Keywords:  Acute kidney injury; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.bcp.2023.115855
Sci Total Environ. 2023 Oct 24. pii: S0048-9697(23)06691-3. [Epub ahead of print] 168064

Polystyrene nanoparticles induced mammalian intestine damage caused by blockage of BNIP3/NIX-mediated mitophagy and gut microbiota alteration.

Yilun Zhang, Zhenzhen Jia, Xianlei Gao, Juan Zhao, Hongyan Zhang.

  Nanoplastics possess the capacity for cellular internalization, and consequentially disrupt mitochondrial functionality, precipitating aberrations in energy metabolism. Given this, the potential accumulation of nanoplastics in alimentary sources presents a considerable hazard to the mammalian gastrointestinal system. While mitophagy serves as a cytoprotective mechanism that sustains redox homeostasis through the targeted removal of compromised mitochondria, the regulatory implications of mitophagy in nanoplastic-induced toxicity remain an underexplored domain. In the present investigation, polystyrene (PS) nanoparticles, with a diameter of 80 nm employed as a representative model to assess their toxicological impact and propensity to instigate mitophagy in intestinal cells both in vitro and in vivo. Data indicated that PS nanoparticles elicited BNIP3/NIX-mediated mitophagy within the intestinal milieu. Strikingly, the impediment of this degradation process at elevated concentrations was correlated with exacerbated pathological ramifications. In vitro assays corroborated that high-dosage cellular uptake of PS nanoparticles obstructed the mitophagy pathway. Furthermore, treatment with PS nanoparticles engendered alterations in gut microbiota composition and manifested a proclivity to modulate nutritional metabolism. Collectively, these findings elucidate that oral exposure to PS nanoparticles culminates in the inhibition of mitophagy and induces perturbations in the intestinal microbiota. This contributes valuable insights into the toxicological repercussions of nanoplastics on mammalian gastrointestinal health.

Keywords:  Gut microbiota; Intestinal toxicity; Mitophagy; Polystyrene nanoparticles

DOI:  https://doi.org/10.1016/j.scitotenv.2023.168064
Front Neurosci. 2023 ;17 1235241

Targeting mitophagy for depression amelioration: a novel therapeutic strategy.

Wangjun Xu, Weiping Gao, Yukun Guo, Feng Xue, Lulu Di, Shaojie Fang, Linlin Fan, Yangyang He, Yunfeng Zhou, Xinmei Xie, Xiaobin Pang.

  Major depressive disorder is a global psychiatric condition characterized by persistent low mood and anhedonia, which seriously jeopardizes the physical and mental well-being of affected individuals. While various hypotheses have been proposed to explicate the etiology of depression, the precise pathogenesis and effective treatment of this disorder remain elusive. Mitochondria, as the primary organelles responsible for cellular energy production, possess the ability to meet the essential energy demands of the brain. Research indicated that the accumulation of damaged mitochondria is associated with the onset of depression. Mitophagy, a type of cellular autophagy, specifically targets and removes excess or damaged mitochondria. Emerging evidence demonstrated that mitophagy dysfunction was involved in the progression of depression, and several pharmacological interventions that stimulating mitophagy exerted excellent antidepressant actions. We provided an overview of updated advancements on the regulatory mechanism of mitophagy and the mitophagy abnormality in depressed patients and animals, as well as in cell models of depression. Meanwhile, various therapeutic strategies to restore mitophagy for depression alleviation were also discussed in this review.

Keywords:  depression; drug therapy; mitochondria; mitophagy; regulatory mechanism

DOI:  https://doi.org/10.3389/fnins.2023.1235241
Biomolecules. 2023 Sep 22. pii: 1435. [Epub ahead of print]13(10):

Autophagy in Parkinson's Disease.

Lior Nechushtai, Dan Frenkel, Ronit Pinkas-Kramarski.

  Parkinson's disease (PD) is a devastating disease associated with accumulation of α-synuclein (α-Syn) within dopaminergic neurons, leading to neuronal death. PD is characterized by both motor and non-motor clinical symptoms. Several studies indicate that autophagy, an important intracellular degradation pathway, may be involved in different neurodegenerative diseases including PD. The autophagic process mediates the degradation of protein aggregates, damaged and unneeded proteins, and organelles, allowing their clearance, and thereby maintaining cell homeostasis. Impaired autophagy may cause the accumulation of abnormal proteins. Incomplete or impaired autophagy may explain the neurotoxic accumulation of protein aggregates in several neurodegenerative diseases including PD. Indeed, studies have suggested the contribution of impaired autophagy to α-Syn accumulation, the death of dopaminergic neurons, and neuroinflammation. In this review, we summarize the recent literature on the involvement of autophagy in PD pathogenesis.

Keywords:  Parkinson’s disease (PD); apolipoprotein E4 (apoE4); autophagy; endocytosis; lysosomal degradation; synuclein α

DOI:  https://doi.org/10.3390/biom13101435
Curr Issues Mol Biol. 2023 Oct 17. 45(10): 8395-8411

Mitochondrial Dysfunction in Dopaminergic Neurons Derived from Patients with LRRK2- and SNCA-Associated Genetic Forms of Parkinson's Disease.

Anna S Vetchinova, Marina R Kapkaeva, Mikhail V Ivanov, Kristina A Kutukova, Natalia M Mudzhiri, Lydia E Frumkina, Anatoly V Brydun, Vladimir S Sukhorukov, Sergey N Illarioshkin.

  Parkinson's disease (PD) is the second most common neurodegenerative disease. Some cases of PD may be caused by genetic factors, among which mutations in the LRRK2 and SNCA genes play an important role. To develop effective neuroprotective strategies for PD, it is important to diagnose the disease at the earliest stages of the neurodegenerative process. Therefore, the detection of diagnostic and prognostic markers of Parkinson's disease (PD) is an urgent medical need. Advances in induced pluripotent stem cell (iPSC) culture technology provide new opportunities for the search for new biomarkers of PD and its modeling in vitro. In our work, we used a new technology for multiplex profiling of gene expression using barcoding on the Nanostring platform to assess the activity of mitochondrial genes on iPSC-derived cultures of dopaminergic neurons obtained from patients with LRRK2- and SNCA-associated genetic forms PD and a healthy donor. Electron microscopy revealed ultrastructural changes in mitochondria in both LRRK2 and SNCA mutant cells, whereas mitochondria in cells from a healthy donor were normal. In a culture with the SNCA gene mutation, the ratio of the area occupied by mitochondria to the total area of the cytoplasm was significantly lower than in the control and in the line with the LRRK2 gene mutation. Transcriptome analysis of 105 mitochondria proteome genes using the Nanostring platform revealed differences between the diseased and normal cells in the activity of genes involved in respiratory complex function, the tricarboxylic acid cycle, ATP production, mitochondria-endoplasmic reticulum interaction, mitophagy, regulation of calcium concentration, and mitochondrial DNA replication.

Keywords:  LRRK2; Parkinson’s disease; SCNA; alpha-synuclein; dardarin; dopaminergic neurons; induced pluripotent stem cells; mitochondria; transcriptomics

DOI:  https://doi.org/10.3390/cimb45100529
Vet Microbiol. 2023 Oct 13. pii: S0378-1135(23)00245-6. [Epub ahead of print]286 109891

Baicalin mitigates nephropathogenic infectious bronchitis virus infection-induced spleen injury via modulation of mitophagy and macrophage polarization in Hy-Line chick.

Guanming Tian, Cheng Huang, Zhengqing Li, Zhihua Lu, Chenlu Feng, Yu Zhuang, Guyue Li, Ping Liu, Guoliang Hu, Xiaona Gao, Xiaoquan Guo.

  Nephropathogenic infectious bronchitis virus (NIBV) infections continue to pose a significant hazard in the poultry industry. Baicalin is a natural flavonoid that has been reported to have antiviral activity, but its function in NIBV infection largely remains unclear. In this study, the antiviral mechanism of baicalin in the spleen of NIBV-infected chicks was mainly elucidated in mitophagy and macrophage polarization. 28-day-old Hy-Line brown chicks were randomly divided into four groups: the group of chicks was treated intranasally (in) with normal saline (0.2 mL) and subsequently divided into two groups: the Con group (basic diet), the Con+BA group (basic diet+10 mg/kg Baicalin); another group of chicks was intranasally infected with SX9 (10-5/0.2 mL) and subsequently divided into two groups: the Dis group (basic diet), the Dis+BA group (basic diet+10 mg/kg Baicalin). Spleen tissues were collected at 3, 7, and 11 days post infection (dpi). NIBV copy number was strikingly decreased in the spleens under BA treatment with infectious time. Histopathological examination showed enlarged and hemorrhagic white pulp and no clearly defined boundary between white pulp and red pulp in the Dis group, which could be improved by BA treatment. Meanwhile, the loss of cristae structure and vacuolization in mitochondria caused by NIBV infection was repaired in the Dis+BA group by ultrastructure observation. In addition, BA treatment inhibited the induction of mitophagy by NIBV infection. BA treatment also promoted innate immunity by enhancing type I IFN levels. Moreover, BA treatment up-regulated M1-related cytokines (iNOS, TNF-α, IL-1β, IL-6) and inhibited M2-related cytokines (ARG2, IL-4, IL-10, Pparg) at the mRNA and protein levels. However, the results from the splenic tissues at 11 dpi are opposite results from 3 and 7 dpi. Immunofluorescence analysis for M1 macrophage marker iNOS and M2 macrophage marker CD163 further validated this result. Collectively, BA inhibited mitophagy and triggered IFN activation, and M1 polarization, which contributed to the inhibition of NIBV infection.

Keywords:  Baicalin; Macrophage polarization; NIBV; PINK1/Parkin-mediated mitophagy; Spleen

DOI:  https://doi.org/10.1016/j.vetmic.2023.109891
Mol Cells. 2023 Oct 23.

Impaired Autophagic Flux in Glucose-Deprived Cells: An Outcome of Lysosomal Acidification Failure Exacerbated by Mitophagy Dysfunction.

Eun Seong Hwang, Seon Beom Song.

  Autophagy dysfunction is associated with human diseases and conditions including neurodegenerative diseases, metabolic issues, and chronic infections. Additionally, the decline in autophagic activity contributes to tissue and organ dysfunction and aging-related diseases. Several factors, such as down-regulation of autophagy components and activators, oxidative damage, microinflammation, and impaired autophagy flux, are linked to autophagy decline. An autophagy flux impairment (AFI) has been implicated in neurological disorders and in certain other pathological conditions. Here, to enhance our understanding of AFI, we conducted a comprehensive literature review of findings derived from two well-studied cellular stress models: glucose deprivation and replicative senescence. Glucose deprivation is a condition in which cells heavily rely on oxidative phosphorylation for ATP generation. Autophagy is activated, but its flux is hindered at the autolysis step, primarily due to an impairment of lysosomal acidity. Cells undergoing replicative senescence also experience AFI, which is also known to be caused by lysosomal acidity failure. Both glucose deprivation and replicative senescence elevate levels of reactive oxygen species (ROS), affecting lysosomal acidification. Mitochondrial alterations play a crucial role in elevating ROS generation and reducing lysosomal acidity, highlighting their association with autophagy dysfunction and disease conditions. This paper delves into the underlying molecular and cellular pathways of AFI in glucose-deprived cells, providing insights into potential strategies for managing AFI that is driven by lysosomal acidity failure. Furthermore, the investigation on the roles of mitochondrial dysfunction sheds light on the potential effectiveness of modulating mitochondrial function to overcome AFI, offering new possibilities for therapeutic interventions.

Keywords:  V-ATPase; autophagy; impairment of autophagy flux; lysosomal acidity; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.14348/molcells.2023.0121
Biomedicines. 2023 Oct 20. pii: 2850. [Epub ahead of print]11(10):

Parkin Promotes Airway Inflammatory Response to Interferon Gamma.

Kris Genelyn Dimasuay, Niccolette Schaunaman, Bruce Berg, Taylor Nichols, Hong Wei Chu.

  PURPOSE: Increased type 2 interferon (i.e., IFN-γ) signaling has been shown to be involved in airway inflammation in a subset of asthma patients who often show high levels of airway neutrophilic inflammation and poor response to corticosteroid treatment. How IFN-γ mediates airway inflammation in a mitochondrial dysfunction setting (e.g., Parkin up-regulation) remains poorly understood. The goal of this study was to determine the role of Parkin, an E3 ubiquitin ligase, in IFN-γ-mediated airway inflammation and the regulation of Parkin by IFN-γ.METHODS: A mouse model of IFN-γ treatment in wild-type and Parkin knockout mice, and cultured human primary airway epithelial cells with or without Parkin gene deficiency were used.
RESULTS: Parkin was found to be necessary for the production of neutrophil chemokines (i.e., LIX and IL-8) and airway neutrophilic inflammation following IFN-γ treatment. Mechanistically, Parkin was induced by IFN-γ treatment both in vivo and in vitro, which was associated with less expression of a Parkin transcriptional repressor Thap11. Overexpression of Thap11 inhibited Parkin expression in IFN-γ-stimulated airway epithelial cells.
CONCLUSIONS: Our data suggest a novel mechanism by which IFN-γ induces airway neutrophilic inflammation through the Thap11/Parkin axis. Inhibition of Parkin expression or activity may provide a new therapeutic target for the treatment of excessive neutrophilic inflammation in an IFN-γ-high environment.

Keywords:  IFN-γ; Parkin; Thap11; inflammation; lung

DOI:  https://doi.org/10.3390/biomedicines11102850