bims-tofagi 2025-04-27 papers

Issue of 2025–04–27
five papers selected by
Michele Frison, University of Cambridge

Autophagy. 2025 Apr 25. 1-3

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

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

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

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

Cell Death Differ. 2025 Apr 23.

TTK promotes mitophagy by regulating ULK1 phosphorylation and pre-mRNA splicing to inhibit mitochondrial apoptosis in bladder cancer.

Kang Chen, Jinyu Chen, Yukun Cong, Qingliu He, Chunyu Liu, Jiawei Chen, Haoran Li, Yunjie Ju, Liang Chen, Yarong Song, Yifei Xing.

Bladder cancer (BC) remains a major global health challenge, with poor prognosis and limited therapeutic options in advanced stages. TTK protein kinase (TTK), a serine/threonine kinase, has been implicated in the progression of various cancers, but its role in BC has not been fully elucidated. In this study, we show that TTK is significantly upregulated in BC tissues and cell lines, correlating with poor patient prognosis. Functional assays revealed that TTK promotes proliferation and inhibits apoptosis of BC cells. Mechanistically, TTK enhances mitophagy by directly phosphorylating ULK1 at Ser477, thereby activating the ULK1/FUNDC1-mediated mitophagy pathway. TTK knockdown disrupts mitophagy, leading to impaired clearance of damaged mitochondria, excessive accumulation of mitochondrial reactive oxygen species (mtROS), and activation of mitochondrial apoptosis. Furthermore, TTK phosphorylates SRSF3 at Ser108, preventing ULK1 exon 5 skipping and maintaining ULK1 mRNA stability. These findings show that TTK plays a key role in maintaining mitophagy in BC cells. Targeting TTK could offer a promising new approach for BC treatment by disrupting mitophagy and inducing mitochondrial apoptosis.

DOI: https://doi.org/10.1038/s41418-025-01492-w

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