bims-tofagi Biomed News
on Mitophagy
Issue of 2025–12–07
six papers selected by
Michele Frison, University of Cambridge
  1. Genetic factors and comorbid pathologies interact to drive regional mitophagy alterations in Lewy body dementia.
  2. Development of a p62 biodegrader for autophagy targeted degradation.
  3. Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.
  4. Comparative analysis of adipose tissue mitophagy and inflammatory markers in obesity and health.
  5. Molecular mechanism of PINK1 regulation by the Hsp90 machinery.
  6. Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
  1. Acta Neuropathol. 2025 Dec 01. 150(1): 59
    Genetic factors and comorbid pathologies interact to drive regional mitophagy alterations in Lewy body dementia.
    Xu Hou, Tyrique Richardson, Michael G Heckman, Fabienne C Fiesel, Launia J White, Shunsuke Koga, Owen A Ross, Dennis W Dickson, Wolfdieter Springer.
      The kinase-ligase pair PINK1-PRKN initiates mitophagy by recognizing and selectively tagging worn-out and dysfunctional mitochondria with phosphorylated ubiquitin (pS65-Ub) to facilitate their elimination via autophagy. In human autopsy brains, the number of pS65-Ub positive cells increases with age but is also associated with Lewy body (LB), neurofibrillary tangles (NFT), and senile plaque (SP) burden. Through a recent genome-wide association study, we identified two genetic modifiers of pS65-Ub levels, APOE4 and ZMIZ1 rs6480922. While LB, NFT, and SP pathologies often coexist in Lewy body dementia (LBD), it is unclear how genetic factors and comorbid neuropathologies interact to impact mitophagy in vulnerable brain regions. We therefore measured levels of the age and disease marker pS65-Ub in the hippocampus and amygdala of 371 LBD cases. Significant and independent associations with pS65-Ub levels were observed for each of the three pathologies LB, NFT, and SP in both regions, and the presence of APOE4 significantly strengthened the association between NFT and pS65-Ub in the hippocampus. While no interaction between LB and SP pathologies was observed regarding association with pS65-Ub, a significant interaction between LB and NFT pathologies on pS65-Ub accumulation was found in the amygdala, which was primarily observed in carriers of the minor allele of ZMIZ1 rs6480922. In summary, our study revealed complex interactions between LB pathology, NFT pathology, and genetic mitophagy modifiers in LBD brains, highlighting potential convergent molecular mechanisms underlying α-synuclein- and tau-associated mitophagy alterations.
    Keywords:  APOE4; Mitochondria; Mitophagy; PARK2; PINK1; Parkin; Tau; Ubiquitin; ZMIZ1; α-Synuclein
    DOI:  https://doi.org/10.1007/s00401-025-02964-6
  2. Nat Commun. 2025 Dec 03. 16(1): 10858
    Development of a p62 biodegrader for autophagy targeted degradation.
    Zacharias Thiel, David Marcellin, Carole Manneville, Benedikt Goretzki, Luca Egger, Rob Maher, Noémie Siccardi, Laura Torres, Alexandra Probst, Catrin S Müller, Nathalie George, Markus Vogel, Sabine Sinterhauf, Alexandra Lavoisier, Ji-Young Choi, Laurianne Forcellino, Alexandro Landshammer, Patrick Hauck, Celine Be, Frédéric Villard, Sascha Gutmann, Marc Meyer, Felix Freuler, Alexandra Hinniger, César Fernández, Suzanne Chau, Maude Patoor, Gilles Sansig, Gabriel Mitchell, Beat Nyfeler.
      Autophagy-based targeted degradation offers a powerful complement to proteasomal degradation leveraging the capacity and versatility of lysosomes to degrade complex cargo. However, it remains unclear which components of the autophagy-lysosomal pathway are most effective for targeted degradation. Here, we describe two orthogonal induced-proximity strategies to identify autophagy effectors capable of degrading organelles and soluble targets. Recruitment of autophagy cargo receptors, ATG8-like proteins, or the kinases ULK1 and TBK1 is sufficient to trigger mitophagy, while only autophagy cargo receptors capable of self-oligomerization degrade soluble cytosolic proteins. We further report a single-domain antibody against p62 and its use as a heterobifunctional degrader to clear mitochondria. Fusing the p62 single-domain antibody to PINK1 enables selective targeting of damaged mitochondria. Our study highlights the importance of avidity for targeted autophagy and suggests that autophagy cargo receptors are attractive entry points for the development of heterobifunctional degraders for organelles or protein aggregates.
    DOI:  https://doi.org/10.1038/s41467-025-65868-9
  3. Acta Neuropathol Commun. 2025 Dec 03.
    Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.
    Eva D Ruiz-Ortega, Anna Wilkaniec, Josué Juárez, Agata Adamczyk.
      Parkinson's disease (PD) is defined by the progressive loss of dopaminergic neurons and the accumulation of misfolded α-synuclein (α-syn), yet the molecular determinants of selective neuronal vulnerability remain unresolved. Increasing evidence implicates mitochondria-and particularly their membranes-as critical platforms where α-syn is toxic. This review highlights how α-syn engages mitochondrial membranes through two interconnected processes: classical aggregation and liquid‒liquid phase separation. Both pathways disrupt membrane architecture, compromise respiratory chain function, and impair mitophagy. A pivotal mediator of these events is cardiolipin (CL), a mitochondria-specific phospholipid essential for cristae organization and quality control pathways. Despite extensive progress, the precise mechanistic contributions of CL to α-syn aggregation, phase transitions, and neuronal degeneration remain poorly defined. Clarifying this interplay is crucial, as CL not only binds α-syn with high affinity but also determines whether it remains in a functional state or progresses toward toxic assemblies. By integrating recent advances, we propose a unifying perspective on CL as a molecular switch at the crossroads of mitochondrial biology, protein aggregation, and phase behavior. Beyond mechanistic insight, this view underscores the potential of CL as a target for the development of mitochondria-directed therapies in PD.
    Keywords:  Alpha-synuclein; Cardiolipin; Liquid‒liquid phase separation; Mitochondrial dysfunction; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40478-025-02190-x
  4. Adipocyte. 2025 Dec;14(1): 2596407
    Comparative analysis of adipose tissue mitophagy and inflammatory markers in obesity and health.
    Shaghayegh Mohammadzadeh, Mitra Nourbakhsh, Parichehreh Yaghmaei, Atefeh Kashanizadeh.
      Obesity is associated with chronic inflammation and disruptions in cellular homeostasis, including impaired autophagy in adipose tissue. This study aimed to investigate the key mitophagy markers in the adipose tissue of individuals with obesity, compared to healthy controls. A total of 60 participants were enrolled, comprising 30 individuals with obesity and 30 healthy controls. Adipose tissue and peripheral blood samples were collected from all participants. Biochemical analyses included measurement of tumor necrosis factor-alpha (TNF-α), leptin, succinate dehydrogenase (SDH), and oxidative stress markers. Gene expression levels of mitophagy-related genes, PARK2, PINK1, and BNIP3L were assessed using quantitative real-time PCR. Additionally, immunohistochemistry was performed to evaluate BNIP3L protein levels in adipose tissue. Compared to the control group, individuals with obesity showed significantly elevated levels of TNF-α and SDH, along with evidence of oxidative stress. Moreover, the expression of PARK2, PINK1, and BNIP3L was significantly upregulated in the obesity group, suggesting increased mitophagy activity in adipose tissue. These findings indicate heightened inflammation and upregulation of mitophagy pathways in the adipose tissue of individuals with obesity. The upregulation of mitophagy-related genes seems to indicate a possible activation of mitophagy-associated pathways in the altered metabolic and inflammatory environment of obesity.
    Keywords:  Obesity; adipose tissue; autophagy; inflammation
    DOI:  https://doi.org/10.1080/21623945.2025.2596407
  5. Nat Commun. 2025 Dec 01. 16(1): 10801
    Molecular mechanism of PINK1 regulation by the Hsp90 machinery.
    Xuyang Tian, Jiayue Su, Ziyi Wang, Tao Liu, Huifang Xiong, Shan Sun, Kunrong Mei, Sen-Fang Sui.
      Hundreds of human kinases, including PINK1-a protein kinase associated with familial Parkinson's disease-are regulated by Hsp90 and its cochaperones. While previous studies have elucidated the mechanism of kinase loading into the Hsp90 machinery, the subsequent regulation of kinases by Hsp90 and its cochaperones remains poorly understood. In this study, using complexes obtained through PINK1 pulldown, we determine the cryo-EM structures of the human Hsp90-Cdc37-PINK1 complex at 2.84 Å, Hsp90-FKBP51-PINK1 at approximately 6 Å, and Hsp90- PINK1 at 2.98 Å. These structures, along with the bound nucleotide in the Hsp90 dimers of the three complexes, provide insights into the Hsp90 chaperone machinery for kinases and elucidate the molecular mechanisms governing cytosolic PINK1 regulation.
    DOI:  https://doi.org/10.1038/s41467-025-65859-w
  6. Nat Commun. 2025 Dec 05.
    Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
    Bowen Liu, Yue Han, Yuan Jin, Meng Ye, Zeliang Yang, Jingyi Yang, Minglu Zhu, Xuyang Zhao, Yan Jin, Yuxin Yin.
      The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-66901-7
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒13 at 12:36.