bims-tofagi 2023-10-01 papers

on Mitophagy

Issue of 2023–10–01
eight papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Ubiquitin Ligase Nrdp1 Controls Autophagy-Associated Acrosome Biogenesis and Mitochondrial Arrangement during Spermiogenesis.
Editorial: Mitochondrial dysfunction as a target in neurodegenerative diseases.
Review of PINK1-Parkin-mediated mitochondrial autophagy in Alzheimer's disease.
Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View.
Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.
Prognostic signature based on mitochondria quality control proteins for the prediction of lung adenocarcinoma patients survival.
Comprehensive analysis of mitophagy-related genes in diagnosis and heterogeneous endothelial cells in chronic rhinosinusitis: based on bulk and single-cell RNA sequencing data.

Cells. 2023 Sep 05. pii: 2211. [Epub ahead of print]12(18):

Ubiquitin Ligase Nrdp1 Controls Autophagy-Associated Acrosome Biogenesis and Mitochondrial Arrangement during Spermiogenesis.

Zi-Yu Luo, Tian-Xia Jiang, Tao Zhang, Ping Xu, Xiao-Bo Qiu.

  Autophagy is critical to acrosome biogenesis and mitochondrial quality control, but the underlying mechanisms remain unclear. The ubiquitin ligase Nrdp1/RNF41 promotes ubiquitination of the mitophagy-associated Parkin and interacts with the pro-autophagic protein SIP/CacyBP. Here, we report that global deletion of Nrdp1 leads to formation of the round-headed sperm and male infertility by disrupting autophagy. Quantitative proteome analyses demonstrated that the expression of many proteins associated with mitochondria, lysosomes, and acrosomes was dysregulated in either spermatids or sperm of the Nrdp1-deficient mice. Deletion of Nrdp1 increased the levels of Parkin but decreased the levels of SIP, the mitochondrial fission protein Drp1 and the mitochondrial protein Tim23 in sperm, accompanied by the inhibition of autophagy, the impairment of acrosome biogenesis and the disruption of mitochondrial arrangement in sperm. Thus, our results uncover an essential role of Nrdp1 in spermiogenesis and male fertility by promoting autophagy, providing important clues to cope with the related male reproductive diseases.

Keywords:  Nrdp1; Parkin; SIP/CacyBP; acrosome; autophagy; mitochondrium; mitophagy; spermiogenesis; ubiquitin ligase

DOI:  https://doi.org/10.3390/cells12182211
Front Mol Neurosci. 2023 ;16 1271175

Editorial: Mitochondrial dysfunction as a target in neurodegenerative diseases.

Lorena Perrone.



Keywords:  DRP1; cell-specific; microglia; mitochondria; mitophagy; neurodegeneration; proteomics; sex-specific

DOI:  https://doi.org/10.3389/fnmol.2023.1271175
Eur J Pharmacol. 2023 Sep 24. pii: S0014-2999(23)00569-1. [Epub ahead of print] 176057

Review of PINK1-Parkin-mediated mitochondrial autophagy in Alzheimer's disease.

Ting-Yuan Zhou, Rui-Xia Ma, Jia Li, Bin Zou, Hui Yang, Rui-Yin Ma, Zi-Qi Wu, Juan Li, Yao Yao.

  Mitochondrial autophagy plays an important role in maintaining the complexity of mitochondrial functions and removing damaged mitochondria, of which the PINK1-Parkin signal pathway is one of the most classical pathways. Thus, a comprehensive and in-depth interpretation of the PINK1-Parkin signal pathway might deepen our understanding on the impacts of mitochondrial autophagy. Alzheimer's disease (AD) is a classical example of neurodegenerative disease. Research on the pathogenesis and treatments of AD has been a focus of scientific research because of its complexity and the limitations of current drug therapies. It was reported that the pathogenesis of AD might be related to mitochondrial autophagy due to excessive deposition of Aβ protein and aggravation of the phosphorylation of Tau protein. Two key proteins in the PINK1-Parkin signaling pathway, PINK1 and Parkin, have important roles in the folding and accumulation of Aβ protein and the phosphorylation of Tau protein. In addition, the intermediate signal molecules in the PINK1-Parkin signal pathway also have certain effects on AD. In this paper, we first described the role of PINK1-Parkin signal pathway on mitochondrial autophagy, then discussed and analyzed the effect of the PINK1-Parkin signal pathway in AD and other metabolic diseases. Our aim was to provide a theoretical direction to further elucidate the pathogenesis of AD and highlight the key molecules related to AD that could be important targets used for AD drug development.

Keywords:  AD; Drugs; Mitochondrial autophagy; Neurodegenerative disease; PINK1-Parkin signal pathway; Signal molecules

DOI:  https://doi.org/10.1016/j.ejphar.2023.176057
Int J Mol Sci. 2023 Sep 08. pii: 13835. [Epub ahead of print]24(18):

Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.

Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Cecilia Bucci, Emanuele Marzetti.

  Mitophagy is crucial for maintaining mitochondrial quality. However, its assessment in vivo is challenging. The endosomal-lysosomal system is a more accessible pathway through which subtypes of extracellular vesicles (EVs), which also contain mitochondrial constituents, are released for disposal. The inclusion of mitochondrial components into EVs occurs in the setting of mild mitochondrial damage and during impairment of lysosomal function. By releasing mitochondrial-derived vesicles (MDVs), cells limit the unload of mitochondrial damage-associated molecular patterns with proinflammatory activity. Both positive and negative effects of EVs on recipient cells have been described. Whether this is due to the production of EVs other than those containing mitochondria, such as MDVs, holding specific biological functions is currently unknown. Evidence on the existence of different MDV subtypes has been produced. However, their characterization is not always pursued, which would be relevant to exploring the dynamics of mitochondrial quality control in health and disease. Furthermore, MDV classification may be instrumental in understanding their biological roles and promoting their implementation as biomarkers in clinical studies.

Keywords:  damage-associated molecular patterns (DAMPs); endosomal–lysosomal system; exosomes; extracellular vesicles; inflammation; mitochondrial DNA; mitochondrial quality control; mitophagy; mitovesicles; oxidative stress

DOI:  https://doi.org/10.3390/ijms241813835
Cells. 2023 Sep 20. pii: 2318. [Epub ahead of print]12(18):

Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View.

Nitesh Sanghai, Geoffrey K Tranmer.

  Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated pathways lead to the progression of neurodegeneration. We present evidence from the past pieces of literature for the most usual global convergent hallmarks like ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, and proteosome networks, and neuroinflammation. Herein, we applied a holistic approach to identify and represent the shared mechanism across NDDs. Further, we believe that this approach could be helpful in identifying key modulators across NDDs, with a particular focus on AD, PD, and ALS. Moreover, these concepts could be applied to the development and diagnosis of novel strategies for diverse NDDs.

Keywords:  Alzheimer’s disease; Parkinson’s disease; ageing; amyotrophic lateral sclerosis; autophagy; calcium butterfly effect; chaperones; excitotoxicity; mitophagy; neurodegenerative diseases; neuroinflammation; oxidative stress; proteostasis

DOI:  https://doi.org/10.3390/cells12182318
Cell Stress Chaperones. 2023 Sep 27.

Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.

Tong Wang, Xinwei Wang, Tong Fu, Yanchun Ma, Qi Wang, Shuxiang Zhang, Xiao Zhang, Hao Zhou, Xing Chang, Ying Tong.

  Myocardial microvessels are composed of a monolayer of endothelial cells, which play a crucial role in maintaining vascular barrier function, luminal latency, vascular tone, and myocardial perfusion. Endothelial dysfunction is a key factor in the development of cardiac microvascular injury and diabetic cardiomyopathy. In addition to their role in glucose oxidation and energy metabolism, mitochondria also participate in non-metabolic processes such as apoptosis, intracellular ion handling, and redox balancing. Mitochondrial dynamics and mitophagy are responsible for regulating the quality and quantity of mitochondria in response to hyperglycemia. However, these endogenous homeostatic mechanisms can both preserve and/or disrupt non-metabolic mitochondrial functions during diabetic endothelial damage and cardiac microvascular injury. This review provides an overview of the molecular features and regulatory mechanisms of mitochondrial dynamics and mitophagy. Furthermore, we summarize findings from various investigations that suggest abnormal mitochondrial dynamics and defective mitophagy contribute to the development of diabetic endothelial dysfunction and myocardial microvascular injury. Finally, we discuss different therapeutic strategies aimed at improving endothelial homeostasis and cardiac microvascular function through the enhancement of mitochondrial dynamics and mitophagy.

Keywords:  Cardiac microvascular injury; Diabetes; Endothelial cells; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1007/s12192-023-01384-3
Cell Death Discov. 2023 Sep 25. 9(1): 352

Prognostic signature based on mitochondria quality control proteins for the prediction of lung adenocarcinoma patients survival.

Anna S Gorbunova, Alexey V Zamaraev, Maria A Yapryntseva, Olga V Kovaleva, Elena M Tchevkina, Maria V Turkina, Boris Zhivotovsky, Gelina S Kopeina.

Lung cancer is the leading cause of cancer mortality worldwide. In recent years, the incidence of lung cancer subtype lung adenocarcinoma (LUAD) has steadily increased. Mitochondria, as a pivotal site of cell bioenergetics, metabolism, cell signaling, and cell death, are often dysregulated in lung cancer cells. Mitochondria maintenance and integrity depend on mitochondrial quality control proteins (MQCPs). During lung cancer progression, the levels of MQCPs could change and promote cancer cell adaptation to the microenvironment and stresses. Here, univariate and multivariate proportional Cox regression analyses were applied to develop a signature based on the level of MQCPs (dimeric form of BNIP3, DRP1, and SIRT3) in tumorous and non-tumorous samples of 80 patients with LUAD. The MQCP signature could be used to separate the patients with LUAD into high- and low-risk groups. Survival analysis indicated that patients in the high-risk group had dramatically shorter overall survival compared with the low-risk patients. Moreover, a nomogram combining clinicopathologic features and the MQCP signature was constructed and validated to predict 1-, 3-, and 5-year overall survival of the patients. Thus, this study presents a novel signature based on MQCPs as a reliable prognostic tool to predict overall survival for patients with LUAD.

DOI: https://doi.org/10.1038/s41420-023-01649-x
Front Genet. 2023 ;14 1228028

Comprehensive analysis of mitophagy-related genes in diagnosis and heterogeneous endothelial cells in chronic rhinosinusitis: based on bulk and single-cell RNA sequencing data.

Shican Zhou, Kai Fan, Ju Lai, Shiwang Tan, Zimu Zhang, Jingwen Li, Xiayue Xu, Chunyan Yao, BoJin Long, Chuanliang Zhao, Shaoqing Yu.

  Background: Chronic rhinosinusitis (CRS) is a complex inflammatory disorder affecting the nasal and paranasal sinuses. Mitophagy, the process of selective mitochondrial degradation via autophagy, is crucial for maintaining cellular balance. However, the role of mitophagy in CRS is not well-studied. This research aims to examine the role of mitophagy-related genes (MRGs) in CRS, with a particular focus on the heterogeneity of endothelial cells (ECs). Methods: We employed both bulk and single-cell RNA sequencing data to investigate the role of MRGs in CRS. We compiled a combined database of 92 CRS samples and 35 healthy control samples from the Gene Expression Omnibus (GEO) database and we explored the differential expression of MRGs between them. A logistic regression model was built based on seven key genes identified through Random Forests and Support Vector Machines - Recursive Feature Elimination (SVM-RFE). Consensus cluster analysis was used to categorize CRS patients based on MRG expression patterns and weighted gene co-expression network analysis (WGCNA) was performed to find modules of highly correlated genes of the different clusters. Single-cell RNA sequencing data was utilized to analyze MRGs and EC heterogeneity in CRS. Results: Seven hub genes-SQSTM1, SRC, UBA52, MFN2, UBC, RPS27A, and ATG12-showed differential expression between two groups. A diagnostic model based on hub genes showed excellent prognostic accuracy. A strong positive correlation was found between the seven hub MRGs and resting dendritic cells, while a significant negative correlation was observed with mast cells and CD8+ T cells. CRS could be divided into two subclusters based on MRG expression patterns. WGCNA analysis identified modules of highly correlated genes of these two different subclusters. At the single-cell level, two types of venous ECs with different MRG scores were identified, suggesting their varying roles in CRS pathogenesis, especially in the non-eosinophilic CRS subtype. Conclusion: Our comprehensive study of CRS reveals the significant role of MRGs and underscores the heterogeneity of ECs. We highlighted the importance of Migration Inhibitory Factor (MIF) and TGFb pathways in mediating the effects of mitophagy, particularly the MIF. Overall, our findings enhance the understanding of mitophagy in CRS, providing a foundation for future research and potential therapeutic developments.

Keywords:  bulk RNA analysis; chronic rhinosinusitis; endothelial cells; mitophagy; single-cell RNA analysis

DOI:  https://doi.org/10.3389/fgene.2023.1228028