bims-tofagi 2025-04-06 papers

bims-tofagi

Biomed News

on Mitophagy

Issue of 2025–04–06
six papers selected by
Michele Frison, University of Cambridge

Conserved components of the macroautophagy machinery in Caenorhabditis elegans.
Beneficial effects of mitophagy enhancers on amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer's disease.
DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.
Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.
Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
Retromer promotes the lysosomal turnover of mtDNA.

Genetics. 2025 Apr 04. pii: iyaf007. [Epub ahead of print]

Conserved components of the macroautophagy machinery in Caenorhabditis elegans.

Hong Zhang, Alicia Meléndez.

  Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and its subsequent delivery to lysosomes for degradation and recycling. In Caenorhabditis elegans, autophagy participates in diverse processes such as stress resistance, cell fate specification, tissue remodeling, aging, and adaptive immunity. Genetic screens in C. elegans have identified a set of metazoan-specific autophagy genes that form the basis for our molecular understanding of steps unique to the autophagy pathway in multicellular organisms. Suppressor screens have uncovered multiple mechanisms that modulate autophagy activity under physiological conditions. C. elegans also provides a model to investigate how autophagy activity is coordinately controlled at an organismal level. In this chapter, we will discuss the molecular machinery, regulation, and physiological functions of autophagy, and also methods utilized for monitoring autophagy during C. elegans development.

Keywords:   C. elegans ; P granules; WormBook; aggrephagy; autophagy; development; dietary restriction; hormesis; lipophagy; longevity; lysophagy; lysosome; mitophagy; xenophagy

DOI:  https://doi.org/10.1093/genetics/iyaf007
Mitochondrion. 2025 Mar 27. pii: S1567-7249(25)00035-2. [Epub ahead of print]83 102038

Beneficial effects of mitophagy enhancers on amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer's disease.

Sudhir Kshirsagar, Arubala P Reddy, P Hemachandra Reddy.

  The purpose of our study is to investigate the beneficial effects of mitophagy enhancers against mutant amyloid precursor protein (APP) and amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Research spanning over two decades highlights the critical role of mitochondrial dysfunction and synaptic damage in the pathogenesis of both early-onset and late-onset AD. Emerging evidence suggests impaired clearance of damaged mitochondria is an early pathological event in AD, positioning mitophagy enhancers as potential therapeutic candidates. This study determined the optimal doses of four mitophagy enhancers-Urolithin A (UA), actinonin, tomatidine, and nicotinamide riboside (NR)-using immortalized mouse hippocampal (HT22) neurons. HT22 cells were transfected with mutant APP (mAPP) cDNA and treated with the enhancers. The effects were assessed by evaluating mRNA and protein expression levels of genes involved in mitochondrial dynamics, biogenesis, mitophagy, and synaptic function, alongside cell survival and mitochondrial respiration. Mitochondrial morphology was also examined in treated and untreated mAPP-HT22 cells. Results showed that mAPP-HT22 cells exhibited increased mitochondrial fission, reduced fusion, downregulated synaptic and mitophagy-related genes, diminished cell survival, impaired mitochondrial respiration, and excessively fragmented, shortened mitochondria. Treatment with mitophagy enhancers reversed these deficits, restoring mitochondrial and synaptic health. Enhanced cell survival, upregulation of mitochondrial fusion, synaptic, and mitophagy genes, improved mitochondrial structure, and reduced fragmentation were observed. Notably, UA demonstrated the most robust mitigating effects. These findings underscore the therapeutic potential of mitophagy enhancers, particularly UA, as promising candidates to treat mitochondrial and synaptic dysfunctions in AD.

Keywords:  Mitochondria; Mitochondrial fragmentation; Mitophagy enhancers; Synaptic activity; UA

DOI:  https://doi.org/10.1016/j.mito.2025.102038
Cell Commun Signal. 2025 Apr 01. 23(1): 158

DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.

Fasih A Rahman, Jasmine M Friedrich Yap, Tyler M Joseph, Amanda M Adam, Sarah M Chapman, Joe Quadrilatero.

   BACKGROUND: Remodeling of the mitochondrial network is implicated in myogenesis. Remodeling processes including mitochondrial fission, mitophagy, and biogenesis are important as they finetune the mitochondrial network to meet the increased energetic demand of myotubes. Evidence suggests that mitochondrial fission governs other mitochondrial remodeling processes; however, this relationship is unclear in the context of myogenesis.
METHODS: We used C2C12 myoblasts to study changes in mitochondrial remodeling processes and their role in regulating myogenesis. To investigate this, we employed genetic manipulation with adenoviruses to modify the levels of key molecules involved in mitochondrial remodeling, including DNM1L, BNIP3, and PPARGC1A.
RESULTS: We demonstrate that overexpression of fission protein DNM1L accelerated mitophagic flux, but reduced myotube size without affecting mitochondrial biogenesis. Conversely, DNM1L knockdown reduced mitophagic flux, impaired myoblast differentiation, and suppressed mitochondrial biogenesis signaling. Additionally, DNM1L knockdown increased mitochondrial apoptotic signaling through CASP9 and CASP3 activation. Attempts to rescue myogenesis through overexpression of the mitophagy receptor BNIP3 or the biogenesis regulator PPARGC1A were unsuccessful in the absence of proper mitochondrial fission. Furthermore, DNM1L overexpression in BNIP3-deficient cells enhanced mitophagic flux, but did not promote myogenesis.
CONCLUSION: These results underscore the complex interdependencies among mitochondrial remodeling processes and highlight the necessity for sequential activation of mitochondrial fission, mitophagy, and biogenesis.

Keywords:  Apoptosis; Mitochondrial biogenesis; Mitochondrial fission; Mitophagy; Myogenesis; Skeletal muscle

DOI:  https://doi.org/10.1186/s12964-025-02142-x
Autophagy. 2025 Mar 31.

Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.

Yuyuan Zhu, Min Cao, Yancheng Tang, Yifan Liu, Haiji Wang, Jiaqi Qi, Cainian Huang, Chenghao Yan, Xu Liu, Sijia Jiang, Yufei Luo, Shaogui Wang, Bo Zhou, Haodong Xu, Ying-Ying Lu, Liming Wang.

  Mitochondria serve as the primary source of intracellular reactive oxygen species (ROS), which play a critical role in orchestrating cell death pathways such as pyroptosis in various types of cancers. PINK1-mediated mitophagy effectively removes damaged mitochondria and reduces detrimental ROS levels, thereby promoting cell survival. However, the regulation of pyroptosis by PINK1 and ROS in neuroblastoma remains unclear. In this study, we demonstrate that inhibition or deficiency of PINK1 sensitizes ROS signaling and promotes pyroptosis in neuroblastoma cells via the BAX-caspase-GSDME signaling pathway. Specifically, inhibition of PINK1 by AC220 or knockout of PINK1 impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Activated BAX facilitates the release of CYCS (cytochrome c, somatic) from the mitochondria into the cytosol, activating CASP3 (caspase 3). Subsequently, activated CASP3 cleaves and activates GSDME, inducing pyroptosis. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression in vivo. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis.

Keywords:  Cell death; GSDME; PINK1; mitochondrial ROS; mitophagy; neuroblastoma

DOI:  https://doi.org/10.1080/15548627.2025.2487037
Free Radic Biol Med. 2025 Apr 01. pii: S0891-5849(25)00196-0. [Epub ahead of print]

Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.

Arunkumar Venkatesan, Marc Ridilla, Nileyma Castro, J Mario Wolosin, Jessica L Henty-Ridilla, Barry E Knox, Preethi S Ganapathy, Jamin S Brown, Anthony F DeVincentis, Sandra Sieminski, Audrey M Bernstein.

  Exfoliation Syndrome is an age-related systemic condition characterized by large aggregated fibrillar material deposition in the anterior eye tissues. This aggregate formation and deposition on the aqueous humor outflow pathway are significant risk factors for developing Exfoliation Glaucoma (XFG). XFG is a multifactorial late-onset disease that shares common features of neurodegenerative diseases, such as increased protein aggregation, impaired protein degradation, and oxidative and cellular stress. XFG patients display decreased mitochondrial membrane potential and mitochondrial DNA deletions. Here, using Tenon Capsule Fibroblasts (TFs) from patients without glaucoma (No Glaucoma, NG) and XFG patients, we found that XFG TFs have impaired mitochondrial bioenergetics and increased reactive oxygen species accumulation. These defects are associated with mitochondrial abnormalities as XFG TFs exhibit smaller mitochondria that contain dysmorphic cristae, with increased mitochondrial localization to lysosomes and slowed mitophagic flux. Mitochondrial dysfunction in the XFG TFs was associated with hyperdynamic microtubules, decreased acetylated tubulin, and increased HDAC6 activity. Treatment of XFG TFs with a mitophagy inducer, Urolithin A, and a mitochondrial biogenesis inducer, Nicotinamide Ribose, improved mitochondrial bioenergetics and reduced ROS accumulation. Our results demonstrate that XFG TFs have abnormal mitochondria and suggest that mitophagy inducers may represent a potential class of therapeutics for reversing mitochondrial dysfunction in XFG patients.

Keywords:  Microtubule cytoskeleton; Mitochondria; Mitophagy; ROS; Tenon fibroblast

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.046
Sci Adv. 2025 Apr 04. 11(14): eadr6415

Retromer promotes the lysosomal turnover of mtDNA.

Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.

Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.

DOI: https://doi.org/10.1126/sciadv.adr6415