bims-tofagi 2025-02-16 papers

bims-tofagi

Biomed News

on Mitophagy

Issue of 2025–02–16
seven papers selected by
Michele Frison, University of Cambridge

Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.
FBXL4-Related Mitochondrial Depletion Syndrome Underscores the role of Mitophagy in Stem Cell Differentiation during Embryogenesis.
Secretory mitophagy: an extracellular vesicle-mediated adaptive mechanism for cancer cell survival under oxidative stress.
TMBIM1 ameliorates sepsis-induced cardiac dysfunction by promoting Parkin-mediated mitophagy.
Predicting Which Mitophagy Proteins Are Dysregulated in Spinocerebellar Ataxia Type 3 (SCA3) Using the Auto-p2docking Pipeline.
Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics.
Mitophagy and Its Significance in Periodontal Disease.

Trends Cell Biol. 2025 Feb 07. pii: S0962-8924(25)00003-0. [Epub ahead of print]

Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.

Michael J Clague, Sylvie Urbé.

  The selective removal of mitochondria by mitophagy proceeds via multiple mechanisms and is essential for human well-being. The PINK1/Parkin and NIX/BNIP3 pathways are strongly linked to mitochondrial dysfunction and hypoxia, respectively. Both are regulated by ubiquitylation and mitochondrial import. Recent studies have elucidated how the ubiquitin kinase PINK1 acts as a sensor of mitochondrial import stress through stable interaction with a mitochondrial import supercomplex. The stability of BNIP3 and NIX is regulated by the SCFFBXL4 ubiquitin ligase complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability is limited by mitochondrial import. Unravelling the functional implications of each mode of mitophagy remains a critical challenge. We propose that mitochondrial import stress prompts a switch between these two pathways.

Keywords:  BNIP3; FBXL4; PINK1; PPTC7; mitophagy; ubiquitin

DOI:  https://doi.org/10.1016/j.tcb.2025.01.003
Stem Cell Rev Rep. 2025 Feb 12.

FBXL4-Related Mitochondrial Depletion Syndrome Underscores the role of Mitophagy in Stem Cell Differentiation during Embryogenesis.

Pankaj Prasun.

  FBXL4- related mitochondrial depletion syndrome is a very rare inherited disorder characterized by global developmental delays, hypotonia, seizures, growth failure, and early onset lactic acidosis. Often, it is associated with structural brain and heart defects, and facial dysmorphism suggesting an embryogenesis defect. FBXL4 encodes F-box and leucine-rich repeat protein 4 (FBXL4) which is involved in mitochondrial quality control and maintenance by regulating mitophagy. A recent study suggests that FBXL4 deficiency leads to increased mitophagy. Fine tuning of mitophagy is essential for stem cell differentiation during embryogenesis. The disruption of this process is the likely explanation of developmental defects in FBXL4- related mitochondrial depletion syndrome.

Keywords:  Embryogenesis; FBXL4; Mitochondria; Mitophagy; Stem cell Differentiation

DOI:  https://doi.org/10.1007/s12015-025-10854-3
Front Cell Dev Biol. 2024 ;12 1490902

Secretory mitophagy: an extracellular vesicle-mediated adaptive mechanism for cancer cell survival under oxidative stress.

Purva V Gade, Angela Victoria Rojas Rivera, Layla Hasanzadah, Sofie Strompf, Thomas Raymond Philipson, Matthew Gadziala, Atharva Tyagi, Arnav Bandam, Rithvik Gabbireddy, Fatah Kashanchi, Amanda Haymond, Lance A Liotta, Marissa A Howard.

  Mitophagy is a critically important survival mechanism in which toxic, aged, or defective mitochondria are segregated into mitophagosomes, which shuttle the damaged mitochondrial segments to the lysosome and proteasome for destruction. Cancer cells rely on mitophagy under conditions of high oxidative stress or increased energy demand. Oxidative stress can generate a large volume of damaged mitochondria, overwhelming lysosomal removal. Accumulated damaged mitochondria are toxic and their proper removal is crucial for maintaining mitochondrial health. We propose a new cancer cell mechanism for survival that is activated when the demand for segregating and eliminating damaged mitochondria exceeds the capacity of the lysosome or proteasome. Specifically, we show that tumor cells subjected to oxidative stress by carbonyl cyanide-3-chlorophenylhdrazone (CCCP) eliminate damaged mitochondria segments by bypassing the lysosome to export them outside the cell via extracellular vesicles (EVs), a process termed "secretory mitophagy". PINK1, the initiator of mitophagy, remains associated with the damaged mitochondria that exported in EVs. Using several types of cancer cells, we show that tumor cells treated with CCCP can be induced to switch over to secretory mitophagy by treatment with Bafilomycin A1, which blocks the fusion of mitophagosomes with lysosomes. Under these conditions, an increased number of PINK1 + EVs are exported. This is associated with greater cell survival by a given CCCP dose, enhanced mitochondrial ATP production, and reduced mitochondrial oxidative damage (membrane depolarization). Our data supports the hypothesis that secretory mitophagy is a previously unexplored process by which cancer cells adapt to survive therapeutic or hypoxic stress. Ultimately, our findings may inform new prevention strategies targeting pre-malignant lesions and therapeutic approaches designed to sensitize tumor cells to oxidative stress-inducing therapies.

Keywords:  PINK1; cancer progression; cell survival; extracellular vesicles; mitophagy; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2024.1490902
FASEB J. 2025 Feb 28. 39(4): e70397

TMBIM1 ameliorates sepsis-induced cardiac dysfunction by promoting Parkin-mediated mitophagy.

Weichang Huang, Anni Lou, Jun Wang, Yuegang Wang, Wenyong Zhang, Jierui Li, Shuanghu Wang, Shiyu Geng, Guozhen Wang, Xu Li.

  Myocardial dysfunction is a significant complication of sepsis that is associated with elevated mortality rates. Transmembrane BAX inhibitor motif containing 1 (TMBIM1), a stress-responsive protein, has garnered interest in the field of cardiovascular disease for its cardioprotective properties. Nevertheless, the role of TMBIM1 on sepsis-induced cardiac dysfunction (SICD) remains unknown. Here, our findings revealed a significant elevation in TMBIM1 expression within the myocardium following endotoxin challenge and further demonstrate the cardioprotective effects of TMBIM1 through adenovirus-mediated gene manipulation. Notably, lipopolysaccharide exposure markedly induced mitochondrial dysfunction in cardiomyocytes, which was effectively alleviated by TMBIM1 overexpression, while TMBIM1 knockdown exacerbated this dysfunction. Moreover, in cardiomyocytes subjected to endotoxin challenge, TMBIM1 was observed to interact with Parkin, facilitating its translocation from the cytosol to damaged mitochondria. This interaction enhanced the activation of mitophagy, thereby promoting the clearance of dysfunctional mitochondria and subsequently mitigating cellular injury. Hence, targeting TMBIM1 could be a novel therapeutic strategy for treating SICD.

Keywords:  Parkin; TMBIM1; mitophagy; myocardial injury; sepsis

DOI:  https://doi.org/10.1096/fj.202402599RR
Int J Mol Sci. 2025 Feb 04. pii: 1325. [Epub ahead of print]26(3):

Predicting Which Mitophagy Proteins Are Dysregulated in Spinocerebellar Ataxia Type 3 (SCA3) Using the Auto-p2docking Pipeline.

Jorge Vieira, Mariana Barros, Hugo López-Fernández, Daniel Glez-Peña, Alba Nogueira-Rodríguez, Cristina P Vieira.

  Dysfunctional mitochondria are present in many neurodegenerative diseases, such as spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD). SCA3/MJD, the most frequent neurodegenerative ataxia worldwide, is caused by the abnormal expansion of the polyglutamine tract (polyQ) at ataxin-3. This protein is known to deubiquitinate key proteins such as Parkin, which is required for mitophagy. Ataxin-3 also interacts with Beclin1 (essential for initiating autophagosome formation adjacent to mitochondria), as well as with the mitochondrial cristae protein TBK1. To identify other proteins of the mitophagy pathway (according to the KEGG database) that can interact with ataxin-3, here we developed a pipeline for in silico analyses of protein-protein interactions (PPIs), called auto-p2docking. Containerized in Docker, auto-p2docking ensures reproducibility and reduces the number of errors through its simplified configuration. Its architecture consists of 22 modules, here used to develop 12 protocols but that can be specified according to user needs. In this work, we identify 45 mitophagy proteins as putative ataxin-3 interactors (53% are novel), using ataxin-3 interacting regions for validation. Furthermore, we predict that ataxin-3 interactors from both Parkin-independent and -dependent mechanisms are affected by the polyQ expansion.

Keywords:  SCA3/MJD; in silico; mitophagy; pipeline

DOI:  https://doi.org/10.3390/ijms26031325
Mol Neurobiol. 2025 Feb 14.

Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics.

Gunel Ayyubova, Leelavathi N Madhu.

  The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1β, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.

Keywords:  Alzheimer’s disease; Autophagy; Microglia; Mitophagy; NLRP3 inflammasome

DOI:  https://doi.org/10.1007/s12035-025-04758-z
Oral Dis. 2025 Feb 10.

Mitophagy and Its Significance in Periodontal Disease.

Guliqihere Abulaiti, Xu Qin, Lili Chen, Guangxun Zhu.

   OBJECTIVES: Periodontal disease is a common chronic inflammatory condition affecting the tissues that support teeth, leading to their destruction. Mitophagy, a specialized form of autophagy responsible for degrading damaged mitochondria, plays a crucial role in maintaining cellular homeostasis. However, its role in periodontal disease progression remains poorly understood. This review aims to summarize recent research on mitophagy's role in periodontal disease pathogenesis.
METHODS: A comprehensive literature review on mitophagy was conducted using PubMed, Scopus, and Web of Science databases, employing keywords related to periodontal disease such as "periodontal," "periodontitis," "gingiva," and "gingivitis."
RESULTS: A review of 18 original studies revealed that mitophagy plays a crucial role in periodontal disease by regulating key pathophysiological mechanisms. Specifically, mitophagy modulates periodontal inflammation by influencing pro-inflammatory cytokines and mitochondrial reactive oxygen species. Additionally, it is essential for alveolar bone remodeling, impacting both bone resorption and regeneration. Mitophagy also regulates cell apoptosis within periodontal tissues, helping to preserve cellular function and tissue integrity during periodontal disease progression.
CONCLUSIONS: Mitophagy regulates periodontal disease pathogenesis by modulating inflammation, bone remodeling, and cell death in periodontal tissues. Further research is needed to explore its therapeutic potential in periodontal disease treatment and improve targeted interventions.

Keywords:  alveolar bone remodeling; apoptosis; inflammation; mitophagy; periodontal disease

DOI:  https://doi.org/10.1111/odi.15279