bims-mitpro 2025-12-14 papers

bims-mitpro

Biomed News

on Mitochondrial proteostasis

Issue of 2025–12–14
six papers selected by
Andreas Kohler, Umeå University

Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
Ubiquitin signaling in PINK1/Parkin-dependent mitophagy.
The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
Retrograde signaling is required for Slm35-mediated negative regulation of mitophagy in yeast.
The transcription factor ANAC017 links mitochondrial retrograde signaling with the ubiquitin-proteasome system to control mitochondrial function in Arabidopsis.
A direct role for a mitochondrial targeting sequence in signalling stress.

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
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
FEBS J. 2025 Dec 07.

The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.

Jiaxin Qian, Annika Nutz, Katja Hansen, Lea Bertgen, Mirita Franz-Wachtel, Boris Macek, Johannes M Herrmann, Doron Rapaport.

  The biogenesis of mitochondria relies on the import of newly synthesized precursor proteins from the cytosol. Tom70 is a mitochondrial surface receptor which recognizes precursors and serves as an interface between mitochondrial protein import and the cytosolic proteostasis network. Mitochondrial import defects trigger a complex stress response, in which compromised protein synthesis rates are a characteristic element. The molecular interplay that connects mitochondrial (dys)function to cytosolic translation rates in yeast cells is however poorly understood. Here, we show that the deletion of the two Tom70 paralogs of yeast (TOM70 and TOM71) leads to defects in mitochondrial biogenesis and slow cell growth. Surprisingly, upon heat stress, the deletion of ZUO1, a chaperone of the ribosome-associated complex (RAC), largely prevented the slow growth and the reduced translation rates in the tom70Δ/tom71Δ double deletion mutant. In contrast, the mitochondrial defects were not cured but even enhanced by ZUO1 deletion. Our study shows that Zuo1 is a critical component in the signaling pathway that mutes protein synthesis upon mitochondrial dysfunction. We propose a novel paradigm according to which RAC serves as a stress-controlled regulatory element of the cytosolic translation machinery.

Keywords:  Tom70; mitochondria; protein import; proteostasis; ribosome‐associated complex

DOI:  https://doi.org/10.1111/febs.70356
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
Plant Commun. 2025 Dec 09. pii: S2590-3462(25)00429-8. [Epub ahead of print] 101667

The transcription factor ANAC017 links mitochondrial retrograde signaling with the ubiquitin-proteasome system to control mitochondrial function in Arabidopsis.

Yang Zhao, Michael Ogden, Ronghui Pan, Jianping Hu, Staffan Persson, Monika W Murcha, Huixia Shou, Yan Wang, Ghazanfar Abbas Khan, James Whelan.

  Mitochondrial biogenesis requires the import of more than a thousand proteins encoded by nuclear DNA. The translocase of the outer mitochondrial membrane (TOM) complex serves as the primary gateway to specifically recognise precursor proteins, which are synthesized in the cytosol. Little is known about the regulation of the abundance of the TOM complex. Using forward genetics we identified key 26S proteasome subunits, including REGULATORY PARTICLE NON-ATPASE1A (RPN1A), that impact TOM complex subunits abundance through the ubiquitin-proteasome pathway. Loss of proteasome function through rpn1a mutation or MG132 treatment increased the abundance of TOM20 isoforms and induced mitochondrial stress marker genes. In contrast, overexpression of ANAC017, an endoplasmic reticulum anchored transcription factor that activates mitochondrial retrograde signaling under stress, lowered TOM20 abundance and reduced mitochondrial protein import. The rate of mitochondrial protein import and respiratory activity was also altered. Genetic analyses placed the proteasome downstream of ANAC017, since the decrease in TOM20 required the RPN1a subunit. Transcriptome profiling under antimycin A showed broad ANAC017 dependent reprogramming of ubiquitin proteasome system genes. A second tier formed by ANAC053 and ANAC078 bound promoters of proteasome subunits, including RPN1a, and was required to restrain TOM20 accumulation. These findings establish a two step transcriptional circuit that engages the ubiquitin proteasome system to tune TOM abundance and coordinate protein import with organelle function.

Keywords:  Mitochondria; Proteasome; Protein turnover; Ubiquitination

DOI:  https://doi.org/10.1016/j.xplc.2025.101667
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