bims-tofagi 2024-12-08 papers

Issue of 2024–12–08
four papers selected by
Michele Frison, University of Cambridge

Cell Death Dis. 2024 Dec 05. 15(12): 881

SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia.

Alice Zhao, Laura Maple, Juwei Jiang, Katie N Myers, Callum G Jones, Hannah Gagg, Connor McGarrity-Cottrell, Ola Rominiyi, Spencer J Collis, Greg Wells, Marufur Rahman, Sarah J Danson, Darren Robinson, Carl Smythe, Chun Guo.

SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia. Furthermore, we identify deSUMO2/3-ylation enzyme SENP3 and mitochondrial Fission protein 1 (FIS1) as key players in hypoxia-induced mitophagy (HIM), with SUMOylatable FIS1 acting as a crucial regulator for SENP3-mediated HIM regulation. Interestingly, we find that hypoxia promotes FIS1 SUMO2/3-ylation and triggers an interaction between SUMOylatable FIS1 and Rab GTPase-activating protein Tre-2/Bub2/Cdc16 domain 1 family member 17 (TBC1D17), which in turn suppresses HIM. Therefore, we propose a novel SUMOylation-dependent pathway where the SENP3-FIS1 axis promotes HIM, with TBC1D17 acting as a fine-tuning regulator. Importantly, the SENP3-FIS1 axis plays a protective role against hypoxia-induced cell death, highlighting its physiological significance, and hypoxia-inducible FIS1-TBC1D17 interaction is detectable in primary glioma stem cell-like (GSC) cultures derived from glioblastoma patients, suggesting its disease relevance. Our findings not only provide new insights into SUMOylation/deSUMOylation regulation of HIM but also suggest the potential of targeting this pathway to enhance cellular resilience under hypoxic stress.

DOI: https://doi.org/10.1038/s41419-024-07271-8

J Biol Chem. 2024 Dec 02. pii: S0021-9258(24)02553-5. [Epub ahead of print] 108051

Structural Basis for the Pathogenicity of Parkin Catalytic Domain Mutants.

Julian P Wagner, Véronique Sauvé, Anshu Saran, Kalle Gehring.

Mutations in the E3 ubiquitin ligase parkin cause a familial form of Parkinson's disease (PD). Parkin and the mitochondrial kinase PINK1 assure quality control of mitochondria through selective autophagy of mitochondria (mitophagy). Whereas numerous parkin mutations have been functionally and structurally characterized, several PD mutations found in the catalytic Rcat domain of parkin remain poorly understood. Here, we characterize two pathogenic Rcat mutants, T415N and P437L. We demonstrate that both mutants exhibit impaired activity using autoubiquitination and ubiquitin vinyl sulfone assays. We determine the minimal ubiquitin binding segment and show that both mutants display impaired binding of ubiquitin charged on the E2 enzyme. Finally, we use AlphaFold 3 to predict a model of the phospho-parkin:phospho-ubiquitin:ubiquitin-charged E2 complex. The model shows the repressor-element of parkin (REP) and the N-terminal residues of the catalytic domain form a helix to position ubiquitin for transfer from the E2 to parkin. Our results rationalize the pathogenicity of the parkin mutations and deepen our understanding of the active parkin-E2∼Ub complex.

DOI: https://doi.org/10.1016/j.jbc.2024.108051

J Biol Chem. 2024 Nov 29. pii: S0021-9258(24)02547-X. [Epub ahead of print] 108045

Quiescent cells maintain active degradation-mediated protein quality control requiring proteasome, autophagy and nucleus-vacuole junctions.

Dina Franić, Mihaela Pravica, Klara Zubčić, Shawna Miles, Antonio Bedalov, Mirta Boban.

Many cells spend a major part of their life in quiescence, a reversible state characterized by a distinct cellular organization and metabolism. In glucose-depleted quiescent yeast cells, there is a metabolic shift from glycolysis to mitochondrial respiration, and a large fraction of proteasomes are reorganized into cytoplasmic granules containing disassembled particles. Given these changes, the operation of protein quality control (PQC) in quiescent cells, in particular the reliance on degradation-mediated PQC and the specific pathways involved, remains unclear. By examining model misfolded proteins expressed in glucose-depleted quiescent yeast cells, we found that misfolded proteins are targeted for selective degradation requiring functional 26S proteasomes. This indicates that a significant pool of proteasomes remains active in degrading quality control substrates. Misfolded proteins were degraded in a manner dependent on the E3 ubiquitin ligases Ubr1 and San1, with Ubr1 playing a dominant role. In contrast to exponentially growing cells, the efficient clearance of certain misfolded proteins additionally required intact nucleus-vacuole junctions (NVJ) and Cue5-independent selective autophagy. Our findings suggest that proteasome activity, autophagy, and NVJ-dependent degradation operate in parallel. Together the data demonstrate that quiescent cells maintain active PQC that relies primarily on selective protein degradation. The necessity of multiple degradation pathways for the removal of misfolded proteins during quiescence underscores the importance of misfolded protein clearance in this cellular state.

Keywords: autophagy; inclusions; nucleus-vacuole junction; proteasome; protein aggregation; protein degradation; protein quality control; quiescence; spatial sequestration; ubiquitin

DOI: https://doi.org/10.1016/j.jbc.2024.108045

Cell Death Discov. 2024 Dec 05. 10(1): 488

Mitophagy in gynecological malignancies: roles, advances, and therapeutic potential.

Jiao Wang, Dandan Wang.

Mitophagy is a process in which impaired or dysfunctional mitochondria are selectively eliminated through the autophagy mechanism to maintain mitochondrial quality control and cellular homeostasis. Based on specific target signals, several mitophagy processes have been identified. Defects in mitophagy are associated with various pathological conditions, including neurodegenerative disorders, cardiovascular diseases, metabolic diseases, and cancer. Mitophagy has been shown to play a critical role in the pathogenesis of gynecological malignancies and the development of drug resistance. In this review, we have summarized and discussed the role and recent advances in understanding the therapeutic potential of mitophagy in the development of gynecological malignancies. Therefore, the valuable insights provided in this review may serve as a basis for further studies that contribute to the development of novel treatment strategies and improved patient outcomes.

DOI: https://doi.org/10.1038/s41420-024-02259-x