bims-tofagi 2025-12-14 papers

Issue of 2025–12–14
five papers selected by
Michele Frison, University of Cambridge

J Mol Neurosci. 2025 Dec 13. 75(4): 162

Ubiquitin-Specific Protease 20 Promotes CCCP-Induced Mitophagy Through Deubiquitination and Stabilization of Serine/Threonine Protein Kinase PINK1.

Ga Hyun Park, Hye In Park, Donghyuk Shin, Kwang Chul Chung.

While Parkinson's disease (PD) is predominantly sporadic, various mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been linked to the autosomal recessive form of PD. PINK1, a serine/threonine protein kinase, holds a pivotal role in mitophagy - a process that selectively eliminates damaged mitochondria, overseeing mitochondrial quality control and ultimately safeguarding against neuronal cell loss in PD. Understanding the regulation of PINK1 stability is essential in comprehending PD pathology, given its involvement in a pro-survival pathway. Although some components of the ubiquitin-proteasome system (UPS) are recognized for mediating the proteolysis of PINK1, the specific enzyme(s) responsible for positively influencing PINK1 stability have remained elusive. In this study, we demonstrated that ubiquitin-specific protease 20 (USP20) functions as a novel deubiquitinating enzyme targeting PINK1. We found that USP20 positively regulates PINK1 levels by hydrolyzing Lys 48-linked polyubiquitin chains, promoting mitophagy under the treatment of mitochondrial depolarizing agent carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Furthermore, CCCP treatment accelerates the deubiquitinating activity of USP20, facilitating the degradation of impaired mitochondria and enhancing mitochondrial quality control via PINK1 accumulation. Taken together, these findings unveil a novel enzyme, USP20, positively impacting PINK1 level and promoting CCCP-induced mitophagy. In addition, this study establishes a comprehensive map depicting how PINK1 can be regulated both positively and negatively through the coordinated action of multiple members in the UPS.

Keywords: CCCP; Deubiquitinating enzyme; Mitophagy; PINK1; Parkinson’s disease; USP20; Ubiquitination

DOI: https://doi.org/10.1007/s12031-025-02457-x

Nature. 2025 Dec 10.

A direct role for a mitochondrial targeting sequence in signalling stress.

Zixuan Yuan, Megan Balzarini, Marina Volpe, Madeleine Goldstein, Tony Shengzhe Peng, Elizabeth Hui, Nancy Neng Fang, Waleed S Albihlal, Melika Hajimohammadi, Kevin Wei, Calvin K Yip, Folkert J van Werven, Thibault Mayor, Hilla Weidberg.

Mitochondrial protein import is required for maintaining organellar function1. Perturbations in this process are associated with various physiological and disease conditions2. Several stress responses, including the mitochondrial compromised protein import response (mitoCPR), combat damage caused by mitochondrial protein import defects2. However, how this defect is sensed remains largely unknown. Here we reveal that the conserved mitochondrial Hsp70 co-chaperone, Mge1, acts as a stress messenger in budding yeast. During mitochondrial stress, unimported Mge1 entered the nucleus and triggered the transcription of mitoCPR target genes. This was mediated by the interaction of Mge1 with the transcription factor Pdr3 on DNA regulatory elements. The mitochondrial targeting sequence of Mge1 was both sufficient and essential for mitoCPR induction, demonstrating that in addition to their roles in mitochondrial protein import, targeting sequences can also function as signalling molecules. As protein import defects are a common consequence of various types of mitochondrial damage3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health.

DOI: https://doi.org/10.1038/s41586-025-09834-x

Biol Open. 2025 Dec 10. pii: bio.062106. [Epub ahead of print]

Retrograde signaling is required for Slm35-mediated negative regulation of mitophagy in yeast.

Hilario Ruelas-Ramírez, Ariann E Mendoza-Martínez, P Abril Medina-Flores, Soledad Funes.

Mitophagy is essential for mitochondrial quality control, selectively removing damaged or superfluous mitochondria to maintain cellular health and metabolic homeostasis. While positive regulators of mitophagy are relatively well characterized, the mechanisms governing its downregulation remain less understood. In this study, we investigate the role of Saccharomyces cerevisiae Slm35-a protein previously involved in oxidative stress response-in the regulation of mitophagy. We discovered that Slm35 is a soluble mitochondrial matrix protein and functions as a novel negative regulator of mitophagy and the mitochondrial retrograde (RTG) signaling pathway. Our results show that Slm35 modulates mitophagy through the RTG pathway, independently of Atg32 proteolytic processing by Yme1 or mitochondrial membrane potential (MMP) dissipation. Notably, Slm35 is crucial for the dynamic regulation of the RTG pathway in mitophagy-inducing conditions. These findings highlight the importance of Slm35 in fine-tuning mitochondrial quality control in response to metabolic cues and suggest a critical role for dynamic RTG pathway regulation in mitophagy control.

Keywords: Atg32; Mitochondria; Mitochondrial retrograde signaling; Mitophagy; Yeast

DOI: https://doi.org/10.1242/bio.062106

J Biochem. 2025 Dec 10. pii: mvaf079. [Epub ahead of print]

Ubiquitin signaling in PINK1/Parkin-dependent mitophagy.

Kei Okatsu, Shuya Fukai.

Mitochondrial quality control plays a critical role in maintaining cellular homeostasis by eliminating dysfunctional mitochondria. The PINK1/Parkin-dependent mitophagy mediates the selective clearance of damaged mitochondria. Dysfunction of PINK1 and Parkin is closely linked to Parkinson's disease. Upon mitochondrial depolarization, PINK1 accumulates on the outer membrane and phosphorylates both ubiquitin and the UBL domain of Parkin to initiate a positive feedback loop of ubiquitination. Parkin catalyzes the assembly of heterogeneous ubiquitin chains on outer mitochondrial membrane proteins, which serve as signals for autophagy adaptors. These adaptors are regulated by kinases such as TANK-binding kinase (TBK1). Deubiquitinating enzymes such as USP30 act as negative regulators. Recent structural and biochemical studies have advanced our understanding of the PINK1/Parkin-dependent mitophagy. Nonetheless, important questions remain regarding the regulatory mechanisms of PINK1, the catalytic mechanism of ubiquitin chain formation by Parkin, and the recognition of ubiquitin chains by autophagy adaptors. Here, we review the current understanding and outstanding questions on the molecular mechanisms underlying the PINK1/Parkin-dependent mitophagy with a focus on ubiquitin signaling.

Keywords: autophagy; kinase; mitophagy; ubiquitin

DOI: https://doi.org/10.1093/jb/mvaf079

Mitochondrion. 2025 Dec 04. pii: S1567-7249(25)00104-7. [Epub ahead of print]87 102107

Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.

Hélène Calais, Giulia Bertolin.

Mitochondrial protein import is necessary to ensure the proper functioning of the organelle of the cell as a whole. More than 1000 proteins are synthesized on cytosolic ribosomes and then imported into mitochondria through translocases such as TOMM and TIMM complexes. Upon entry, they can reach their final mitochondrial compartment, namely the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix. In this review, we will first explore the main mitochondrial protein import mechanisms. Then, we will focus on how import deficiencies may trigger stress paradigms. Stress response pathways are activated to restore correct cellular homeostasis. We will explore four interconnected pathways at the cellular or mitochondrial scale, which can compensate for import alterations. These are the DELE1-HRI axis combined with the ISR, the UPRam, the UPRmt, and mitophagy. Their activation depends on the extent of import alteration, with ISR and UPRmt pathways activated in conditions of low stress. If stress levels are too high, the elimination of dysfunctional mitochondria by mitophagy is triggered. Last, we will explore how mitochondrial import deficiencies are a feature common to multifaceted pathologies, such as neurodegenerative diseases and cancer. We will also present pharmacological compounds mimicking stress response mechanisms and that could be used as a therapeutic option in the near future to restore efficient mitochondrial protein import rates. Overall, this review highlights the critical role of mitochondrial protein import in cellular and mitochondrial stress response, and in disease pathogenesis. It also emphasizes the potential of mitochondrial protein import as a therapeutic target, despite the surprising absence of direct pharmacological treatments to date.

Keywords: DELE1/HRI; ISR; Mitochondrial protein import; Pharmacological modulation; UPRam; UPRmt

DOI: https://doi.org/10.1016/j.mito.2025.102107