bims-tofagi 2024-03-17 papers

on Mitophagy

Issue of 2024–03–17
six papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia.
Mitophagy defect mediates the aging-associated hallmarks in Hutchinson-Gilford progeria syndrome.
GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes.
Yeast Bxi1/Ybh3 mediates conserved mitophagy and apoptosis in yeast and mammalian cells: convergence in Bcl-2 family.
Role of PTEN-Induced Protein Kinase 1 as a Mitochondrial Dysfunction Regulator in Cardiovascular Disease Pathogenesis.
Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria.

Nat Commun. 2024 Mar 13. 15(1): 2264

NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia.

Chih-Wei Chen, Chi Su, Chang-Yu Huang, Xuan-Rong Huang, Xiaojing Cuili, Tung Chao, Chun-Hsiang Fan, Cheng-Wei Ting, Yi-Wei Tsai, Kai-Chien Yang, Ti-Yen Yeh, Sung-Tsang Hsieh, Yi-Ju Chen, Yuxi Feng, Tony Hunter, Zee-Fen Chang.

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family localized on the mitochondrial outer membrane (MOM). Here, we report a role of NME3 in hypoxia-induced mitophagy dependent on its active site phosphohistidine but not the NDPK function. Mice carrying a knock-in mutation in the Nme3 gene disrupting NME3 active site histidine phosphorylation are vulnerable to ischemia/reperfusion-induced infarction and develop abnormalities in cerebellar function. Our mechanistic analysis reveals that hypoxia-induced phosphatidic acid (PA) on mitochondria is essential for mitophagy and the interaction of DRP1 with NME3. The PA binding function of MOM-localized NME3 is required for hypoxia-induced mitophagy. Further investigation demonstrates that the interaction with active NME3 prevents DRP1 susceptibility to MUL1-mediated ubiquitination, thereby allowing a sufficient amount of active DRP1 to mediate mitophagy. Furthermore, MUL1 overexpression suppresses hypoxia-induced mitophagy, which is reversed by co-expression of ubiquitin-resistant DRP1 mutant or histidine phosphorylatable NME3. Thus, the site-specific interaction with active NME3 provides DRP1 a microenvironment for stabilization to proceed the segregation process in mitophagy.

DOI: https://doi.org/10.1038/s41467-024-46385-7
Aging Cell. 2024 Mar 14. e14143

Mitophagy defect mediates the aging-associated hallmarks in Hutchinson-Gilford progeria syndrome.

Yingying Sun, Le Xu, Yi Li, Shunze Jia, Gang Wang, Xufeng Cen, Yuyan Xu, Zhongkai Cao, Jingjing Wang, Ning Shen, Lidan Hu, Jin Zhang, Jianhua Mao, Hongguang Xia, Zhihong Liu, Xudong Fu.

  Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for aging. The cellular machinery mediating age-associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-associated phenotypes of HGPS-MSCs by inhibiting the STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI-77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging-associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging-associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.

Keywords:  HGPS; UMI-77; aging; mitophagy

DOI:  https://doi.org/10.1111/acel.14143
Cells. 2024 Mar 04. pii: 448. [Epub ahead of print]13(5):

GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes.

Qiang Zhu, Matthew E Combs, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.

  Cardiomyocytes rely on proper mitochondrial homeostasis to maintain contractility and achieve optimal cardiac performance. Mitochondrial homeostasis is controlled by mitochondrial fission, fusion, and mitochondrial autophagy (mitophagy). Mitophagy plays a particularly important role in promoting the degradation of dysfunctional mitochondria in terminally differentiated cells. However, the precise mechanisms by which this is achieved in cardiomyocytes remain opaque. Our study identifies GRAF1 as an important mediator in PINK1-Parkin pathway-dependent mitophagy. Depletion of GRAF1 (Arhgap26) in cardiomyocytes results in actin remodeling defects, suboptimal mitochondria clustering, and clearance. Mechanistically, GRAF1 promotes Parkin-LC3 complex formation and directs autophagosomes to damaged mitochondria. Herein, we found that these functions are regulated, at least in part, by the direct binding of GRAF1 to phosphoinositides (PI(3)P, PI(4)P, and PI(5)P) on autophagosomes. In addition, PINK1-dependent phosphorylation of Parkin promotes Parkin-GRAF1-LC3 complex formation, and PINK1-dependent phosphorylation of GRAF1 (on S668 and S671) facilitates the clustering and clearance of mitochondria. Herein, we developed new phosphor-specific antibodies to these sites and showed that these post-translational modifications are differentially modified in human hypertrophic cardiomyopathy and dilated cardiomyopathy. Furthermore, our metabolic studies using serum collected from isoproterenol-treated WT and GRAF1CKO mice revealed defects in mitophagy-dependent cardiomyocyte fuel flexibility that have widespread impacts on systemic metabolism. In summary, our study reveals that GRAF1 co-regulates actin and membrane dynamics to promote cardiomyocyte mitophagy and that dysregulation of GRAF1 post-translational modifications may underlie cardiac disease pathogenesis.

Keywords:  GRAF1; PINK1-Parkin pathway; cardiomyocytes; metabolism; mitophagy

DOI:  https://doi.org/10.3390/cells13050448
Biol Chem. 2024 Mar 12.

Yeast Bxi1/Ybh3 mediates conserved mitophagy and apoptosis in yeast and mammalian cells: convergence in Bcl-2 family.

Yuying Wang, Zhiyuan Hu, Maojun Jiang, Yanxin Zhang, Linjie Yuan, Ziqian Wang, Ting Song, Zhichao Zhang.

  The process of degrading unwanted or damaged mitochondria by autophagy, called mitophagy, is essential for mitochondrial quality control together with mitochondrial apoptosis. In mammalian cells, pan-Bcl-2 family members including conical Bcl-2 members and non-conical ones are involved in and govern the two processes. We have illustrated recently the BH3 receptor Hsp70 interacts with Bim to mediate both apoptosis and mitophagy. However, whether similar pathways exist in lower eukaryotes where conical Bcl-2 members are absent remained unclear. Here, a specific inhibitor of the Hsp70-Bim PPI, S1g-10 and its analogs were used as chemical tools to explore the role of yeast Bxi1/Ybh3 in regulating mitophagy and apoptosis. Using Om45-GFP processing assay, we illustrated that yeast Ybh3 mediates a ubiquitin-related mitophagy pathway in both yeast and mammalian cells through association with Hsp70, which is in the same manner with Bim. Moreover, by using Bax/Bak double knockout MEF cells, Ybh3 was identified to induce apoptosis through forming oligomerization to trigger mitochondrial outer membrane permeabilization (MOMP) like Bax. We not only illustrated a conserved ubiquitin-related mitophagy pathway in yeast but also revealed the multi-function of Ybh3 which combines the function of BH3-only protein and multi-domain Bax protein as one.

Keywords:  Bxi1/Ybh3; Hsp70; mitophagy; ubiquitin

DOI:  https://doi.org/10.1515/hsz-2023-0359
Vasc Specialist Int. 2024 Mar 15. 40 9

Role of PTEN-Induced Protein Kinase 1 as a Mitochondrial Dysfunction Regulator in Cardiovascular Disease Pathogenesis.

Jun Gyo Gwon, Seung Min Lee.

  Cardiovascular disease (CVD) remains a global health challenge, primarily due to atherosclerosis, which leads to conditions such as coronary artery disease, cerebrovascular disease, and peripheral arterial disease. Mitochondrial dysfunction initiates endothelial dysfunction, a key contributor to CVD pathogenesis, as well as triggers the accumulation of reactive oxygen species (ROS), energy stress, and cell death in endothelial cells, which are crucial for atherosclerosis development. This review explores the role of PTEN-induced protein kinase 1 (PINK1) in mitochondrial quality control, focusing on its significance in cardiovascular health. PINK1 plays a pivotal role in mitophagy (selective removal of damaged mitochondria), contributing to the prevention of CVD progression. PINK1-mediated mitophagy also affects the maintenance of cardiomyocyte homeostasis in ischemic heart disease, thus mitigating mitochondrial dysfunction and oxidative stress, as well as regulates endothelial health in atherosclerosis through influencing ROS levels and inflammatory response. We also investigated the role of PINK1 in vascular smooth muscle cells, emphasizing on its role in apoptosis and atherosclerosis. Dysfunctional mitophagy in these cells accelerates cellular senescence and contributes to adverse effects including plaque rupture and inflammation. Mitophagy has also been explored as a potential therapeutic target for vascular calcification, a representative lesion in atherosclerosis, with a focus on lactate-induced mechanisms. Finally, we highlight the current research and clinical trials targeting mitophagy as a therapeutic avenue for CVD.

Keywords:  Cardiovascular disease; Endothelial dysfunction; Mitophagy; PTEN-induced protein kinase 1; Vascular calcification

DOI:  https://doi.org/10.5758/vsi.230116
FEBS J. 2024 Mar 11.

Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria.

Sara Al Rawi, Lorna Simpson, Guðrún Agnarsdóttir, Neil Q McDonald, Veronika Chernuha, Orly Elpeleg, Massimo Zeviani, Roger A Barker, Ronen Spiegel, Heike Laman.

  Mutations in FBXO7 have been discovered to be associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerisation domain of Fbxo7. This alteration selectively ablates the Fbxo7-PI31 interaction and causes a significant reduction in Fbxo7 and PI31 levels in patient cells. Consistent with their association with proteasomes, patient fibroblasts have reduced proteasome activity and proteasome subunits. We also show PI31 interacts with the MiD49/51 fission adaptor proteins, and unexpectedly, PI31 acts to facilitate SCFFbxo7 -mediated ubiquitination of MiD49. The L250P mutation reduces the SCFFbxo7 ligase-mediated ubiquitination of a subset of its known substrates. Although MiD49/51 expression was reduced in patient cells, there was no effect on the mitochondrial network. However, patient cells show reduced levels of mitochondrial function and mitophagy, higher levels of ROS and are less viable under stress. Our study demonstrates that Fbxo7 and PI31 regulate proteasomes and mitochondria and reveals a new function for PI31 in enhancing the SCFFbxo7 E3 ubiquitin ligase activity.

Keywords:  E3 ubiquitin ligase; Fbxo7/PARK15; Parkinson's disease; mitochondria; proteasome

DOI:  https://doi.org/10.1111/febs.17114