bims-mitpro 2025-04-27 papers

bims-mitpro

Biomed News

on Mitochondrial proteostasis

Issue of 2025–04–27
eight papers selected by
Andreas Kohler, Umeå University

Mitochondrial Proteases and Their Roles in Mitophagy in Plants, Animals, and Yeast.
Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.
Krüppel-like factors in mitochondrial quality control.
Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.
UPRmt alleviates bone cancer pain through the restoration of mitochondrial function.
SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.
TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.

Plant Cell Physiol. 2025 Apr 23. pii: pcaf038. [Epub ahead of print]

Mitochondrial Proteases and Their Roles in Mitophagy in Plants, Animals, and Yeast.

Kacper Ludwig, Małgorzata Heidorn-Czarna.

  Mitochondria play a central role in cellular respiration and other essential metabolic and signaling pathways. To function properly, mitochondria require the maintenance of proteostasis-a balance between protein synthesis and degradation. This balance is achieved through the mitochondrial protein quality control (mtPQC) system, which includes mitochondrial proteases and mitophagy. Mitochondrial proteases ensure proper protein sorting within the mitochondria and maintain proteome homeostasis by degrading unassembled, damaged, or short-lived regulatory proteins. Numerous studies have demonstrated the critical role of mitochondrial proteases in regulating mitophagy-the selective degradation of damaged, aging, or excess mitochondria or their fragments via autophagy. Notably, the rhomboid PARL protease is involved in ubiquitin-dependent PINK1-Parkin mitophagy in mammals while the i-AAA protease Yme1 plays a role in mitophagy in budding yeast. Despite the conservation of core autophagy genes, knowledge about the molecular mechanisms and protein regulators of mitophagy in plants remains limited. In this review, we discuss recent advances in understanding the roles of mitochondrial proteases and mitophagy across plants, animals, and yeast. By comparing these mechanisms across kingdoms, we highlight the potential regulatory function of the plant i-AAA mitochondrial protease in controlling mitophagy, providing new insights into mitochondrial protein quality control networks in plants.

Keywords:   Arabidopsis thaliana ; i-AAA protease; mitochondria; mitochondrial proteases; mitochondrial protein quality control system; mitophagy

DOI:  https://doi.org/10.1093/pcp/pcaf038
Mitochondrion. 2025 Apr 17. pii: S1567-7249(25)00037-6. [Epub ahead of print]84 102040

Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.

Isabel Amador-Martínez, Ana Karina Aranda-Rivera, Mauricio Raziel Martínez-Castañeda, José Pedraza-Chaverri.

  Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms to maintain mitochondrial quality control (MQC) and functions. In contrast, the perturbation of these mechanisms has been associated with the pathogenesis of several diseases. Thus, targeting specific pathways within MQC could offer a therapeutic avenue for protecting mitochondrial integrity. However, the mechanisms related to MQC and mitochondrial stress signaling in the cardio-renal axis have been poorly explored. The primary limitations include the lack of reproducibility in the experimental models of cardio-renal disease, the incomplete knowledge of molecules that generate bidirectional damage, and the temporality of the study models. Therefore, we believe that integration of all of those limitations, along with recent advances in MQC mechanisms (i.e., mitophagy), stress signaling pathways (e.g., integrated stress response, mitochondrial unfolded protein response, and mitochondrial protein import), associated pharmacology, and targeted therapeutic approaches could reveal what the deregulation of these mechanisms is like and provide ideas for generating strategies that seek to avoid the progression of cardio-renal diseases.

Keywords:  Cardio-renal disease; Integrated stress response; Mitochondrial dysfunction; Mitochondrial import; Mitochondrial quality control; Mitochondrial unfolded protein response

DOI:  https://doi.org/10.1016/j.mito.2025.102040
Front Physiol. 2025 ;16 1554877

Krüppel-like factors in mitochondrial quality control.

M Y Zhang, H Zhang, Y M Yao, D W Yang.

  Krüppel-like factors (KLFs) are a group of transcription factors characterized by conserved zinc finger domains in the C-terminus, which are critically involved in basic cellular processes, including growth, differentiation, apoptosis, and angiogenesis, and play important roles in many pathophysiological responses. Mitochondrial homeostasis relies on a coordinated mitochondrial quality control system, which maintains the number and morphological stability and coordinates mitochondrial physiological functions through renewal and self-clearance. In this paper, we review the current advances of KLFs in mitochondrial quality control (MQC), including the potential roles and regulatory mechanisms in mitochondrial biogenesis, mitochondrial fusion/fission, mitophagy and mitochondrial unfolded protein response. We also introduce the specific pharmacological modulation of KLFs, expecting to transforming basic research achievements and providing the possibility of targeted therapy for KLFs.

Keywords:  Krüppel-like factors; mitochondrial biogenesis; mitochondrial fusion/fission; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy

DOI:  https://doi.org/10.3389/fphys.2025.1554877
Curr Biol. 2025 Apr 21. pii: S0960-9822(25)00296-9. [Epub ahead of print]35(8): R287-R290

Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.

Mohamed A Eldeeb, Michael Shahid, Edward A Fon.

Dysregulation of mitochondrial protein import induces significant cellular stress. Yet, our understanding of the dialogue between mitochondrial import, the stress it can trigger, and counteracting mechanisms remains incomplete. A recent study unveils how the mitochondrial protease YME1L1 degrades unoccupied mitochondrial translocases during mitochondrial import stress.

DOI: https://doi.org/10.1016/j.cub.2025.03.011
J Mol Biol. 2025 Apr 21. pii: S0022-2836(25)00227-X. [Epub ahead of print] 169161

Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.

Bishal Basak, Erika L F Holzbaur.

  Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.

Keywords:  PINK1; Parkin; autophagosomes; lysosomes; mitochondria; mitophagy; neurodegeneration

DOI:  https://doi.org/10.1016/j.jmb.2025.169161
Exp Cell Res. 2025 Apr 22. pii: S0014-4827(25)00164-8. [Epub ahead of print]448(2): 114568

UPRmt alleviates bone cancer pain through the restoration of mitochondrial function.

Dan Li, Mingming Xie, Haohao Zeng, Jiacheng Yu, Rui Xu, Zhen Wang, Yulin Huang, Yan Yang, Yu'e Sun.

  The mitochondrial unfolded protein response (UPRmt) is an intracellular retrograde signaling process that facilitates the restoration of mitochondrial homeostasis. Mitochondria are essential for neuronal signaling, and their dysfunction has been implicated as a significant mechanism in the development of chronic pain. Nevertheless, little is known about the exact function of UPRmt in bone cancer pain (BCP). This research intended to explore the connection between UPRmt and the progression of BCP. In BCP group, the ultrastructure of spinal cord mitochondria was disrupted, accompanied by a decline in ATP levels and a decrease in Mitochondrial membrane potential (MMP). Concurrently, mRNA and protein levels of UPRmt marker proteins (Atf5, Hsp60, LonP1, and ClpP) were upregulated, with the expression of Atf5, a key transcription factor of UPRmt, notably enhanced in spinal dorsal horn neurons. Nicotinamide riboside (NR)-mediated pharmacological augmentation of the UPRmt significantly alleviated BCP-induced nociceptive hypersensitivity, as demonstrated by elevated mechanical withdrawal thresholds and diminished spontaneous flinching behavior. Concomitant mitochondrial functional recovery was evidenced by restoration of MMP and normalization of ATP level. Notably, genetic knockdown of activating transcription factor 5 (Atf5) abolished both NR-induced UPRmt activation and the consequent protection against rotenone-mediated mitochondrial dysfunction. These findings establish UPRmt potentiation as an effective strategy for ameliorating mitochondrial dysfunction and attenuating BCP-associated nociception, proposing this pathway as a novel therapeutic target for clinical pain management.

Keywords:  Bone cancer pain; Mitochondria; Mitochondrial unfolded protein response

DOI:  https://doi.org/10.1016/j.yexcr.2025.114568
Autophagy. 2025 Apr 25. 1-3

SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.

Mingzhu Tang, Guang Lu, Han-Ming Shen.

  Mitophagy, selective degradation of dysfunctional mitochondria by the autophagy-lysosome pathway, is critical for maintaining cellular homeostasis. In recent years, significant progress has been made in understanding how PINK1 (PTEN-induced kinase 1)-mediated phosphorylation and the E3 ubiquitin (Ub) ligase (PRKN/parkin)-mediated ubiquitination form a positive feedforward loop in control of mitophagy. Nevertheless, a fundamental question remains: How is PINK1 transcriptionally modulated under mitochondrial stress to finely support mitophagy? Recently, we unveiled a novel mechanism in control of PINK1 transcription by SMAD3 (SMAD family member 3), an essential component of the TGFB/TGFβ (transforming growth factor beta)-SMAD signaling pathway. Upon mitochondrial depolarization, SMAD3 is activated through PINK1-mediated phosphorylation of SMAD3 at serine 423/425 independent of canonical TGFB signaling. More importantly, the SMAD3-PINK1 regulatory axis appears to functionally provide a pro-survival mechanism against mitochondrial stress. Therefore, PINK1 and SMAD3 constitute a newly discovered positive feedforward loop to regulate mitophagy, highlighting the need for further exploring the crosstalk between TGFB-SMAD signaling and mitophagy.

Keywords:  Mitophagy; PINK1; SMAD3; phosphorylation; transcription

DOI:  https://doi.org/10.1080/15548627.2025.2496364
Nat Chem Biol. 2025 Apr 22.

TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.

Anat Raiff, Shidong Zhao, Aizat Bekturova, Colin Zenge, Shir Mazor, Xinyan Chen, Wenwen Ru, Yaara Makaros, Tslil Ast, Alban Ordureau, Chao Xu, Itay Koren.

Mitochondrial homeostasis is maintained through complex regulatory mechanisms, including the balance of mitochondrial dynamics involving fusion and fission processes. A central player in this regulation is the ubiquitin-proteasome system (UPS), which controls the degradation of pivotal mitochondrial proteins. In this study, we identified cullin-RING E3 ligase 2 (CRL2) and its substrate receptor, FEM1B, as critical regulators of mitochondrial dynamics. Through proteomic analysis, we demonstrate here that FEM1B controls the turnover of PLD6, a key regulator of mitochondrial dynamics. Using structural and biochemical approaches, we show that FEM1B physically interacts with PLD6 and that this interaction is facilitated by the direct association of FEM1B with the mitochondrial import receptor TOM20. Ablation of FEM1B or disruption of the FEM1B-TOM20 interaction impairs PLD6 degradation and induces mitochondrial defects, phenocopying PLD6 overexpression. These findings underscore the importance of FEM1B in maintaining mitochondrial morphology and provide further mechanistic insights into how the UPS regulates mitochondrial homeostasis.

DOI: https://doi.org/10.1038/s41589-025-01894-4