bims-mitpro 2024-06-02 papers

Issue of 2024–06–02
three papers selected by
Andreas Kohler, Umeå University

Cell Rep. 2024 May 29. pii: S2211-1247(24)00622-3. [Epub ahead of print]43(6): 114294

TBK1 is ubiquitinated by TRIM5α to assemble mitophagy machinery.

Bhaskar Saha, Hallvard Olsvik, Geneva L Williams, Seeun Oh, Gry Evjen, Eva Sjøttem, Michael A Mandell.

Ubiquitination of mitochondrial proteins provides a basis for the downstream recruitment of mitophagy machinery, yet whether ubiquitination of the machinery itself contributes to mitophagy is unknown. Here, we show that K63-linked polyubiquitination of the key mitophagy regulator TBK1 is essential for its mitophagy functions. This modification is catalyzed by the ubiquitin ligase TRIM5α and is required for TBK1 to interact with and activate a set of ubiquitin-binding autophagy adaptors including NDP52, p62/SQSTM1, and NBR1. Autophagy adaptors, along with TRIM27, enable TRIM5α to engage with TBK1 following mitochondrial damage. TRIM5α's ubiquitin ligase activity is required for the accumulation of active TBK1 on damaged mitochondria in Parkin-dependent and Parkin-independent mitophagy pathways. Our data support a model in which TRIM5α provides a mitochondria-localized, ubiquitin-based, self-amplifying assembly platform for TBK1 and mitophagy adaptors that is ultimately necessary for the recruitment of the core autophagy machinery.

Keywords: CP: Cell biology; NBR1; NDP52; Optineurin; TAX1BP1; TBK1; TRIM27/RFP; autophagy; p62; tripartite motif; ubiquitin ligase

DOI: https://doi.org/10.1016/j.celrep.2024.114294

J Mol Biol. 2024 May 29. pii: S0022-2836(24)00226-2. [Epub ahead of print] 168631

FIP200 phosphorylation regulates late steps in mitophagy.

Christopher Eickhorst, Riccardo Babic, Jorrell Rush-Kittle, Leon Lucya, Fatimah Lami Imam, Pablo Sánchez-Martín, David M Hollenstein, Jonas Michaelis, Christian Münch, Chris Meisinger, Dea Slade, Laura Gámez-Díaz, Claudine Kraft.

Mitophagy is a specific type of autophagy responsible for the selective elimination of dysfunctional or superfluous mitochondria, ensuring the maintenance of mitochondrial quality control. The initiation of mitophagy is coordinated by the ULK1 kinase complex, which engages mitophagy receptors via its FIP200 subunit. Whether FIP200 performs additional functions in the subsequent later phases of mitophagy beyond this initial step and how its regulation occurs, remains unclear. Our findings reveal that multiple phosphorylation events on FIP200 differentially control the early and late stages of mitophagy. Furthermore, these phosphorylation events influence FIP200's interaction with ATG16L1. In summary, our results highlight the necessity for precise and dynamic regulation of FIP200, underscoring its importance in the progression of mitophagy.

Keywords: ATG16L1; Atg1/ULK1 kinase complex; FIP200; autophagy; mitophagy

DOI: https://doi.org/10.1016/j.jmb.2024.168631

Int J Med Sci. 2024 ;21(7): 1204-1212

Targeting Cancer Mitochondria by Inducing an Abnormal Mitochondrial Unfolded Protein Response Leads to Tumor Suppression.

Baoxiao Wang, Wenjun Chen, Qiqi Huang, Ye Chen, Yajing Wang.

The mitochondrial unfolded protein response (UPRmt) is a pivotal cellular mechanism that ensures mitochondrial homeostasis and cellular survival under stress conditions. This study investigates the role of UPRmt in modulating the response of nasopharyngeal carcinoma cells to cisplatin-induced stress. We report that the inhibition of UPRmt via AEB5F exacerbates cisplatin cytotoxicity, as evidenced by increased lactate dehydrogenase (LDH) release and apoptosis, characterized by a surge in TUNEL-positive cells. Conversely, the activation of UPRmt with oligomycin attenuates these effects, preserving cell viability and reducing apoptotic markers. Immunofluorescence assays reveal that UPRmt activation maintains mitochondrial membrane potential and ATP production in the presence of cisplatin, countering the rise in reactive oxygen species (ROS) and inhibiting caspase-9 activation. These findings suggest that UPRmt serves as a cytoprotective mechanism in cancer cells, mitigating cisplatin-induced mitochondrial dysfunction and apoptosis. The data underscore the therapeutic potential of modulating UPRmt to improve the efficacy and reduce the side effects of cisplatin chemotherapy. This study provides a foundation for future research on the exploitation of UPRmt in cancer treatment, with the aim of enhancing patient outcomes by leveraging the cellular stress response pathways.

Keywords: mitochondria, cisplatin, oxidative stress; mitochondrial unfolded protein response; nasopharyngeal carcinoma

DOI: https://doi.org/10.7150/ijms.95624