bims-tofagi 2023-09-17 papers

on Mitophagy

Issue of 2023–09–17
twelve papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

PA2G4/EBP1 ubiquitination by PRKN/PARKIN promotes mitophagy protecting neuron death in cerebral ischemia.
Mitochondrial degradation: Mitophagy and beyond.
Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.
Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.
Insulin-like growth factor binding protein-3 mediates hyperosmolar stress-induced mitophagy through the mechanistic target of rapamycin.
Parkin-mediated mitophagy protects against aluminum trichloride-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.
Deciphering the implications of mitophagy-related signatures in clinical outcomes and microenvironment heterogeneity of clear cell renal cell carcinoma.
The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease.
Integrative analysis of the prognostic value and immune microenvironment of mitophagy-related signature for multiple myeloma.
Alternative to lysosomal degradation: mitochondrial removal via EVs.
Correction to: Mitophagy activation repairs Leber's hereditary optic neuropathy-associated mitochondrial dysfunction and improves cell survival.
Correction to: ``Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease''.

Autophagy. 2023 Sep 15.

PA2G4/EBP1 ubiquitination by PRKN/PARKIN promotes mitophagy protecting neuron death in cerebral ischemia.

Inwoo Hwang, Byeong-Seong Kim, Ho Yun Lee, Sung-Woo Cho, Seung Eun Lee, Jee-Yin Ahn.

  Cerebral ischemia induces massive mitochondrial damage, leading to neuronal death. The elimination of damaged mitochondria via mitophagy is critical for neuroprotection. Here we show that the level of PA2G4/EBP1 (proliferation-associated 2G4) was notably increased early during transient middle cerebral artery occlusion and prevented neuronal death by eliciting cerebral ischemia-reperfusion (IR)-induced mitophagy. Neuron-specific knockout of Pa2g4 increased infarct volume and aggravated neuron loss with impaired mitophagy and was rescued by introduction of adeno-associated virus serotype 2 expressing PA2G4/EBP1. We determined that PA2G4/EBP1 is ubiquitinated on lysine 376 by PRKN/PARKIN on the damaged mitochondria and interacts with receptor protein SQSTM1/p62 for mitophagy induction. Thus, our study suggests that PA2G4/EBP1 ubiquitination following cerebral IR-injury promotes mitophagy induction, which may be implicated in neuroprotection.

Keywords:  Ischemia; PA2G4/EBP1; PRKN/PARKIN; SQSTM1/p62; mitophagy

DOI:  https://doi.org/10.1080/15548627.2023.2259215
Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]

Mitochondrial degradation: Mitophagy and beyond.

Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.

  Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.

Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
Free Radic Biol Med. 2023 Sep 13. pii: S0891-5849(23)00627-5. [Epub ahead of print]

Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.

Sharadha Dayalan Naidu, Plamena R Angelova, Elena V Knatko, Chiara Leonardi, Miroslav Novak, Laureano de la Vega, Ian G Ganley, Andrey Y Abramov, Albena T Dinkova-Kostova.

Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the principal determinant of the cellular redox homeostasis, contributing to mitochondrial function, integrity and bioenergetics. The main negative regulator of Nrf2 is Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor for Cul3/Rbx1 ubiquitin ligase, which continuously targets Nrf2 for ubiquitination and proteasomal degradation. Loss-of-function mutations in Keap1 occur frequently in lung cancer, leading to constitutive Nrf2 activation. We used the human lung cancer cell line A549 and its CRISPR/Cas9-generated homozygous Nrf2-knockout (Nrf2-KO) counterpart to assess the role of Nrf2 on mitochondrial health. To confirm that the observed effects of Nrf2 deficiency are not due to clonal selection or long-term adaptation to the absence of Nrf2, we also depleted Nrf2 by siRNA (siNFE2L2), thus creating populations of Nrf2-knockdown (Nrf2-KD) A549 cells. Nrf2 deficiency decreased mitochondrial respiration, but increased the mitochondrial membrane potential, mass, DNA content, and the number of mitolysosomes. The proportion of ATG7 and ATG3 within their respective LC3B conjugates was increased in Nrf2-deficient cells with mutant Keap1, whereas the formation of new autophagosomes was not affected. Thus, in lung cancer cells with loss-of-function Keap1, Nrf2 facilitates mitolysosome degradation thereby ensuring timely clearance of damaged mitochondria.

DOI: https://doi.org/10.1016/j.freeradbiomed.2023.09.009
Redox Biol. 2023 Sep 07. pii: S2213-2317(23)00272-0. [Epub ahead of print]67 102871

Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.

Senyu Yao, Mao Pang, Yanheng Wang, Xiaokang Wang, Yaobang Lin, Yanyan Lv, Ziqi Xie, Jianfeng Hou, Cong Du, Yuan Qiu, Yuanjun Guan, Bin Liu, Jiancheng Wang, Andy Peng Xiang, Limin Rong.

  Ferroptosis is a newly discovered form of iron-dependent oxidative cell death and drives the loss of neurons in spinal cord injury (SCI). Mitochondrial damage is a critical contributor to neuronal death, while mitochondrial quality control (MQC) is an essential process for maintaining mitochondrial homeostasis to promote neuronal survival. However, the role of MQC in neuronal ferroptosis has not been clearly elucidated. Here, we further demonstrate that neurons primarily suffer from ferroptosis in SCI at the single-cell RNA sequencing level. Mechanistically, disordered MQC aggravates ferroptosis through excessive mitochondrial fission and mitophagy. Furthermore, mesenchymal stem cells (MSCs)-mediated mitochondrial transfer restores neuronal mitochondria pool and inhibits ferroptosis through mitochondrial fusion by intercellular tunneling nanotubes. Collectively, these results not only suggest that neuronal ferroptosis is regulated in an MQC-dependent manner, but also fulfill the molecular mechanism by which MSCs attenuate neuronal ferroptosis at the subcellular organelle level. More importantly, it provides a promising clinical translation strategy based on stem cell-mediated mitochondrial therapy for mitochondria-related central nervous system disorders.

Keywords:  Intercellular mitochondrial transfer; Mesenchymal stem cells; Mitochondrial quality control; Neuronal ferroptosis; Spinal cord injury

DOI:  https://doi.org/10.1016/j.redox.2023.102871
J Biol Chem. 2023 Sep 08. pii: S0021-9258(23)02267-6. [Epub ahead of print] 105239

Insulin-like growth factor binding protein-3 mediates hyperosmolar stress-induced mitophagy through the mechanistic target of rapamycin.

Whitney Stuard Sambhariya, Ian J Trautmann, Danielle M Robertson.

Hyperosmolarity of the ocular surface triggers inflammation and pathological damage in dry eye disease (DED). In addition to a reduction in quality of life, DED causes vision loss and when severe, blindness. Mitochondrial dysfunction occurs as a consequence of hyperosmolar stress. We have previously reported on a role for the insulin-like growth factor binding protein-3 (IGFBP-3) in the regulation of mitochondrial ultrastructure and metabolism in mucosal surface epithelial cells; however, this appears to be context specific. Due to the finding that IGFBP-3 expression is decreased in response to hyperosmolar stress in vitro and in an animal model of DED, we next sought to determine whether the hyperosmolar stress-mediated decrease in IGFBP-3 alters mitophagy, a key mitochondrial quality control mechanism. Here we show that hyperosmolar stress induces mitophagy through differential regulation of BNIP3L/NIX and PINK1-mediated pathways. In corneal epithelial cells, this was independent of p62. The addition of exogenous IGFBP-3 abrogated the increase in mitophagy. This occurred through regulation of mTOR, highlighting the existence of a new IGFBP-3-mTOR signaling pathway. Together, these findings support a novel role for IGFBP-3 in mediating mitochondrial quality control in DED and have broad implications for epithelial tissues subject to hyperosmolar stress and other mitochondrial diseases.

DOI: https://doi.org/10.1016/j.jbc.2023.105239
Ecotoxicol Environ Saf. 2023 Sep 11. pii: S0147-6513(23)00963-6. [Epub ahead of print]264 115459

Parkin-mediated mitophagy protects against aluminum trichloride-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.

Siming Huo, Xuliang Zhang, Jinyu Xu, Jian Zhang, Jiayu Du, Bo Li, Miao Song, Bing Shao, Yanfei Li, Feibo Xu.

  Aluminum is a neurotoxic food contaminant. Aluminum trichloride (AlCl3) causes hippocampal mitochondrial damage, leading to hippocampal injury. Damaged mitochondria can release mitochondrial reactive oxygen species (mtROS) and activate nucleotide-binding oligomerization domain-like receptor-containing 3 (NLRP3) inflammasomes and apoptosis. E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy can attenuate mitochondrial damage. However, the role of mitophagy in AlCl3-induced mice hippocampal damage and its regulatory mechanism remain elusive. First, C57BL/6 N mice were treated with 0, 44.825, 89.65, and 179.3 mg/kg body weight AlCl3 drinking water for 90 d. Apoptosis, NLRP3-inflammasome activation and mitochondrial damage were increased in AlCl3-induced hippocampal damage. In addition, Parkin-mediated mitophagy peaked in the middle-dose group and was slightly attenuated in the high-dose group. Subsequently, we used wild-type and Parkin knockout (Parkin-/-) mice to investigate the AlCl3-induced hippocampal damage. The results showed that Parkin-/- inhibited mitophagy, and aggravated AlCl3-induced mitochondrial damage, NLRP3-inflammasome activation, apoptosis and hippocampal damage. Finally, we administered MitoQ (mtROS inhibitor) and MCC950 (NLRP3 inhibitor) to AlCl3-treated Parkin-/- mice to investigate the mechanism of Parkin-mediated mitophagy. The results showed that inhibition of mtROS and NLRP3 attenuated hippocampal NLRP3-inflammasome activation, apoptosis, and damage in AlCl3-treated Parkin-/- mice. These findings indicate that Parkin-mediated mitophagy protects against AlCl3-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.

Keywords:  Aluminum; Mitochondrial reactive oxygen species; Mitophagy; NLRP3-inflammasome; Neurodegenerative diseases; Parkin

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115459
J Cancer Res Clin Oncol. 2023 Sep 09.

Deciphering the implications of mitophagy-related signatures in clinical outcomes and microenvironment heterogeneity of clear cell renal cell carcinoma.

Jianfeng Xiang, Wangrui Liu, Shifan Liu, Tao Wang, Haidan Tang, Jianfeng Yang.

   BACKGROUND: The role of mitophagy in various cancer-associated biological processes is well recognized. Nonetheless, the comprehensive implications of mitophagy in clear cell renal cell carcinoma (ccRCC) necessitate further exploration.
METHODS: Based on the transcriptomic data encompassing 25 mitophagy-related genes (MRGs), we identified the distinct mitophage patterns in 763 ccRCC samples. Subsequently, a mitophage-related predictive signature with machine learning algorithms was constructed, designated as RiskScore, to quantify the individual mitophagy status in ccRCC patients. Employing multispectral immunofluorescence (mIF) and immunohistochemistry (IHC) staining, we detected the effect of PTEN-induced putative kinase 1 (PINK1) in the prognosis and immune microenvironment of ccRCC.
RESULTS: Our analysis initially encompassed a comprehensive assessment of the expression profiling, genomic variations, and interactions among the 25 MRGs in ccRCC. Subsequently, the consensus clustering algorithm was applied to stratify ccRCC patients into three clusters with distinct prognostic outcomes, tumor microenvironment (TME) characteristics, and underlying biological pathways. We screened eight pivotal genes (CLIC4, PTPRB, SLC16A12, ENPP5, FLRT3, HRH2, PDK4, and SCD5) to construct a mitophagy-related predictive signature, which showed excellent prognostic value for ccRCC patients. Moreover, patient subgroups divided by the RiskScore showed contrasting expression levels of immune checkpoints (ICPs), abundance of immune cells, and immunotherapy response. Additionally, a nomogram was established with robust predictive power integrating the RiskScore and clinical features. Notably, we observed that PINK1 expression markedly correlated with favorable treatment response and advanced maturation stages of tertiary lymphoid structures, which potentially shed light on enhancing anti-tumor immunity of ccRCC.
CONCLUSION: Collectively, this study initially developed a signature associated with mitophagy, which demonstrated an excellent ability to predict the clinical prognosis, TME characterization, and responsiveness to targeted therapy and immunotherapy for ccRCC patients. Of particular note is the pivotal role of PINK1 in mediating the treatment response and immune microenvironment for ccRCC patients.

Keywords:  Clear cell renal cell carcinoma; Immunotherapy response; Mitophagy; PINK1; Prognosis; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00432-023-05349-y
Neuromolecular Med. 2023 Sep 12.

The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease.

Yu Liang, Guangshang Zhong, Mingxin Ren, Tingting Sun, Yangyang Li, Ming Ye, Caiyun Ma, Yu Guo, Changqing Liu.

  Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.

Keywords:  Mitophagy; Parkinson's disease; Ubiquitin proteasome system

DOI:  https://doi.org/10.1007/s12017-023-08755-0
BMC Cancer. 2023 Sep 12. 23(1): 859

Integrative analysis of the prognostic value and immune microenvironment of mitophagy-related signature for multiple myeloma.

Yachun Jia, Rui Liu, Luyi Shi, Yuandong Feng, Linlin Zhang, Ni Guo, Aili He, Guangyao Kong.

   BACKGROUND: Multiple myeloma (MM) is a fatal malignant tumor in hematology. Mitophagy plays vital roles in the pathogenesis and drug sensitivity of MM.
METHODS: We acquired transcriptomic expression data and clinical index of MM patients from NCI public database, and 36 genes involved in mitophagy from the gene set enrichment analysis (GSEA) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was conducted to construct a risk score prognostic model. Kaplan-Meier survival analysis and receiver operation characteristic curves (ROC) were conducted to identify the efficiency of prognosis and diagnosis. ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA) was performed to uncover the level of immune infiltration. QRT-PCR was performed to verify gene expression in clinical samples of MM patients. The sensitivity to chemotherapy drugs was evaluated upon the database of the genomics of drug sensitivity in cancer (GDSC).
RESULTS: Fifty mitophagy-related genes were differently expressed in two independent cohorts. Ten out of these genes were identified to be related to MM overall survival (OS) rate. A prognostic risk signature model was built upon on these genes: VDAC1, PINK1, VPS13C, ATG13, and HUWE1, which predicted the survival of MM accurately and stably both in training and validation cohorts. MM patients suffered more adverse prognosis showed more higher risk core. In addition, the risk score was considered as an independent prognostic element for OS of MM patients by multivariate cox regression analysis. Functional pathway enrichment analysis of differentially expressed genes (DEGs) based on risk score showed terms of cell cycle, immune response, mTOR pathway, and MYC targets were obviously enriched. Furthermore, MM patients with higher risk score were observed lower immune scores and lower immune infiltration levels. The results of qRT-PCR verified VDAC1, PINK1, and HUWE1 were dysregulated in new diagnosed MM patients. Finally, further analysis indicated MM patients showed more susceptive to bortezomib, lenalidomide and rapamycin in high-risk group.
CONCLUSION: Our research provided a neoteric prognostic model of MM based on mitophagy genes. The immune infiltration level based on risk score paved a better understanding of the participation of mitophagy in MM.

Keywords:  Immune infiltration; Mitophagy; Multiple myeloma; Nomogram; Prognosis; Risk signature

DOI:  https://doi.org/10.1186/s12885-023-11371-7
Nat Rev Mol Cell Biol. 2023 Sep 11.

Alternative to lysosomal degradation: mitochondrial removal via EVs.

Paulina Strzyz.

DOI: https://doi.org/10.1038/s41580-023-00660-5
Hum Mol Genet. 2023 Sep 12. pii: ddad148. [Epub ahead of print]

Correction to: Mitophagy activation repairs Leber's hereditary optic neuropathy-associated mitochondrial dysfunction and improves cell survival.

DOI: https://doi.org/10.1093/hmg/ddad148
Hum Mol Genet. 2023 Sep 09. pii: ddad147. [Epub ahead of print]

Correction to: ``Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease''.

DOI: https://doi.org/10.1093/hmg/ddad147