bims-tofagi 2024-06-09 papers

Nat Commun. 2024 Jun 04. 15(1): 4740

Burkholderia pseudomallei BipD modulates host mitophagy to evade killing.

Dongqi Nan, Chenglong Rao, Zhiheng Tang, Wenbo Yang, Pan Wu, Jiangao Chen, Yupei Xia, Jingmin Yan, Wenzheng Liu, Ziyuan Zhang, Zhiqiang Hu, Hai Chen, Yaling Liao, Xuhu Mao, Xiaoyun Liu, Quanming Zou, Qian Li.

Mitophagy is critical for mitochondrial quality control and function to clear damaged mitochondria. Here, we found that Burkholderia pseudomallei maneuvered host mitophagy for its intracellular survival through the type III secretion system needle tip protein BipD. We identified BipD, interacting with BTB-containing proteins KLHL9 and KLHL13 by binding to the Back and Kelch domains, recruited NEDD8 family RING E3 ligase CUL3 in response to B. pseudomallei infection. Although evidently not involved in regulation of infectious diseases, KLHL9/KLHL13/CUL3 E3 ligase complex was essential for BipD-dependent ubiquitination of mitochondria in mouse macrophages. Mechanistically, we discovered the inner mitochondrial membrane IMMT via host ubiquitome profiling as a substrate of KLHL9/KLHL13/CUL3 complex. Notably, K63-linked ubiquitination of IMMT K211 was required for initiating host mitophagy, thereby reducing mitochondrial ROS production. Here, we show a unique mechanism used by bacterial pathogens that hijacks host mitophagy for their survival.

DOI: https://doi.org/10.1038/s41467-024-48824-x

Sci Adv. 2024 Jun 07. 10(23): eadn7191

Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.

Olawale G Raimi, Hina Ojha, Kenneth Ehses, Verena Dederer, Sven M Lange, Cristian Polo Rivera, Tom D Deegan, Yinchen Chen, Melanie Wightman, Rachel Toth, Karim P M Labib, Sebastian Mathea, Neil Ranson, Rubén Fernández-Busnadiego, Miratul M K Muqit.

Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson's disease (PD). Stabilization of PINK1 at the translocase of outer membrane (TOM) complex of damaged mitochondria is critical for its activation. The mechanism of how PINK1 is activated in the TOM complex is unclear. Here, we report that co-expression of human PINK1 and all seven TOM subunits in Saccharomyces cerevisiae is sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit toward PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modeling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These findings will aid in the development of small-molecule activators of PINK1 as a therapeutic strategy for PD.

DOI: https://doi.org/10.1126/sciadv.adn7191

Front Pharmacol. 2024 ;15 1389953

The structure and function of FUN14 domain-containing protein 1 and its contribution to cardioprotection by mediating mitophagy.

Yuhu Lv, Zhengze Yu, Peiwen Zhang, Xiqian Zhang, Huarui Li, Ting Liang, Yanju Guo, Lin Cheng, Fenglin Peng.

Cardiovascular disease (CVD) is a serious public health risk, and prevention and treatment efforts are urgently needed. Effective preventive and therapeutic programs for cardiovascular disease are still lacking, as the causes of CVD are varied and may be the result of a multifactorial combination. Mitophagy is a form of cell-selective autophagy, and there is increasing evidence that mitophagy is involved in cardioprotective processes. Recently, many studies have shown that FUN14 domain-containing protein 1 (FUNDC1) levels and phosphorylation status are highly associated with many diseases, including heart disease. Here, we review the structure and functions of FUNDC1 and the path-ways of its mediated mitophagy, and show that mitophagy can be effectively activated by dephosphorylation of Ser13 and Tyr18 sites, phosphorylation of Ser17 site and ubiquitination of Lys119 site in FUNDC1. By effectively activating or inhibiting excessive mitophagy, the quality of mitochondria can be effectively controlled. The main reason is that, on the one hand, improper clearance of mitochondria and accumulation of damaged mitochondria are avoided, and on the other hand, excessive mitophagy causing apoptosis is avoided, both serving to protect the heart. In addition, we explore the possible mechanisms by which FUNDC1-mediated mitophagy is involved in exercise preconditioning (EP) for cardioprotection. Finally, we also point out unresolved issues in FUNDC1 and its mediated mitophagy and give directions where further research may be needed.

Keywords: FUN14 domain-containing protein 1; cardioprotection; exercise preconditioning; mitochondria; mitophagy

DOI: https://doi.org/10.3389/fphar.2024.1389953

J Biochem. 2024 Jun 06. pii: mvae042. [Epub ahead of print]

Comprehensive analysis of non-selective and selective autophagy in yeast atg mutants and characterization of autophagic activity in the absence of the Atg8 conjugation system.

Tamara Ginevskaia, Aleksei Innokentev, Kentaro Furukawa, Tomoyuki Fukuda, Manabu Hayatsu, Shun-Ichi Yamashita, Keiichi Inoue, Shinsuke Shibata, Tomotake Kanki.

Most autophagy-related genes, or ATG genes, have been identified in studies using budding yeast. Although the functions of the ATG genes are well understood, the contributions of individual genes to non-selective and various types of selective autophagy remain to be fully elucidated. In this study, we quantified the activity of non-selective autophagy, the cytoplasm-to-vacuole targeting (Cvt) pathway, mitophagy, endoplasmic reticulum (ER)-phagy, and pexophagy in all Saccharomyces cerevisiae atg mutants. Among the mutants of the core autophagy genes considered essential for autophagy, the atg13 mutant and mutants of the genes involved in the two ubiquitin-like conjugation systems retained residual autophagic functionality. In particular, mutants of the Atg8 ubiquitin-like conjugation system (the Atg8 system) exhibited substantial levels of non-selective autophagy, the Cvt pathway, and pexophagy, although mitophagy and ER-phagy were undetectable. Atg8-system mutants also displayed intravacuolar vesicles resembling autophagic bodies, albeit at significantly reduced size and frequency. Thus, our data suggest that membranous sequestration and vacuolar delivery of autophagic cargo can occur in the absence of the Atg8 system. Alongside these findings, the comprehensive analysis conducted here provides valuable datasets for future autophagy research.

Keywords: Atg8 conjugation system; Cvt pathway; autophagy; core autophagy genes; mitophagy

DOI: https://doi.org/10.1093/jb/mvae042