bims-tofagi Biomed News
on Mitophagy
Issue of 2026–04–19
seven papers selected by
Michele Frison, University of Cambridge
  1. Pestiviruses utilize pyrimidine metabolism to regulate mitophagy for viral replication.
  2. A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.
  3. Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
  4. FTMT-mediated suppression of mitophagy links iron accumulation to osteoporosis.
  5. Mitophagy promotes lung repair and regeneration by restoring epithelial metabolic fitness.
  6. Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.
  7. Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from parkinsonism to perinatal lethality.
  1. Autophagy. 2026 Apr 12.
    Pestiviruses utilize pyrimidine metabolism to regulate mitophagy for viral replication.
    Bingqian Zhao, Jing Chen, Yan Cheng, Yuhang Li, Linhan Zhong, Jinxia Chen, Xiaoqing Bi, Jishan Bai, Qi Dai, Yinbo Ye, Linke Zou, Li Wang, Bin Zhou.
      DHODH (dihydroorotate dehydrogenase (quinone)) has been demonstrated as a critical regulator of programmed cell death, yet its role in macroautophagy/autophagy remains poorly defined. Flaviviridae pose a significant threat to global public health, and their replication is closely associated with autophagy. Building upon our previous findings that DHODH is a broad-spectrum target for Flaviviridae and a key regulator of Pestiviruses replication, this study employed RNA-seq screening coupled with functional validation to demonstrate that DHODH affects Pestiviruses replication by regulating mitophagy. Notably, we observed remarkable virus genus specificity in this regulatory mechanism. For autophagy-dependent Pestiviruses, DHODH deficiency impaired autophagosome-lysosome fusion, thereby suppressing viral replication. Conversely, in autophagy-inhibiting Flaviviruses, the blockade of autophagy flux facilitated viral replication. These observations underscore the specificity of DHODH-mediated viral replication regulation. Additionally, compound supplementation assays indicated that DHODH regulated autophagy via pyrimidine nucleotide metabolism, as exogenous pyrimidine precursors restored autophagosome-lysosome fusion. Furthermore, our research uncovered a novel mechanism whereby classical swine fever virus (CSFV) non-structural protein 4A (NS4A) recruited DHODH to mitochondria, facilitating its interaction with MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) through the LC3-interacting region (LIR) domain to activate mitophagy. Collectively, our findings highlight DHODH as a promising antiviral target within the metabolism-autophagy axis, providing novel insights for antiviral drug development.
    Keywords:  Autolysosome formation; CSFV; DHODH; LIR; mitophagy; viral non-structural proteins
    DOI:  https://doi.org/10.1080/15548627.2026.2659305
  2. J Cell Sci. 2026 Apr 13. pii: jcs.264577. [Epub ahead of print]
    A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.
    Riccardo Babic, Leon Lucya, Christoph Reiter, Franziska Kriegenburg, Ramón Castellanos-Martínez, David M Hollenstein, Florian Becker, Carola Hunte, Claudine Kraft.
      Mitophagy, the selective degradation of damaged mitochondria, preserves mitochondrial quality, yet how mitochondrial fission is coordinated with autophagy initiation remains unclear. Here we identify the mitochondrial outer membrane protein MTFR1L as a key component of mitophagy initiation hubs after using a synthetic FKBP-FRB system to tether ULK1 kinase to mitochondria independently of damage. We find that MTFR1L is enriched at ULK1 foci together with additional fission factors and constitutive mitochondrial targeting of MTFR1L shifts mitochondrial morphology towards fragmentation. MTFR1L depletion decreases respiratory capacity, elevates apoptosis, and impairs mitophagy flux. Upon mitophagy induction, MTFR1L is phosphorylated in a ULK1 kinase-dependent manner, and reciprocally modulates ULK1 activity, establishing a feedback loop. Moreover, MTFR1L is required for proper ATG13 stability. These findings position MTFR1L as a critical link between mitochondrial fission and the autophagy machinery, coordinating mitophagy initiation and cell survival.
    Keywords:  ATG13; Autophagy; MTFR1L; Mitophagy; ULK1
    DOI:  https://doi.org/10.1242/jcs.264577
  3. Trends Biochem Sci. 2026 Apr 16. pii: S0968-0004(26)00061-7. [Epub ahead of print]
    Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
    Andrew N Bayne, Jean-François Trempe.
      PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration into broader cellular signaling networks. This review synthesizes these insights, focusing on the molecular determinants of PINK1/Parkin activation and the regulatory crosstalk that integrates mitophagy with other cellular stress responses. These mechanistic advances position the PINK1/Parkin pathway as a promising, tractable therapeutic target for Parkinson's disease and related pathologies.
    Keywords:  PINK1; Parkin; Parkinson’s disease; mitochondrial quality control (MQC); mitophagy; stress response; therapeutic development
    DOI:  https://doi.org/10.1016/j.tibs.2026.02.014
  4. Redox Biol. 2026 Apr 06. pii: S2213-2317(26)00155-2. [Epub ahead of print]93 104157
    FTMT-mediated suppression of mitophagy links iron accumulation to osteoporosis.
    Ruizhi Zhang, Yike Wang, Lei Li, Junjie Li, Guangchen Feng, Yutong Hu, Gongwen Liu, Xiongyi Wang, Jiajun Zhang, Peng Wei, Houfu Lai, Keyu Zhu, Xiao Wang, Xueqin Gao, Wen Wei, Yixuan Fang, Jianrong Wang, Na Yuan, Youjia Xu.
      Primary osteoporosis is a major age-related disease with a significant global health burden. While iron accumulation is a known risk factor, the mechanisms linking it to bone loss remain unclear. Here, we report that impaired mitophagy in bone marrow mesenchymal stem cells (BMSCs) is a hallmark of osteoporosis and is critically exacerbated by iron accumulation. We found that iron accumulation in BMSCs inhibits mitophagy, leading to mitochondrial dysfunction, increased oxidative stress, and cellular senescence, ultimately impairing osteogenic differentiation. Importantly, targeted activation of mitophagy, either pharmacologically or genetically, restored mitochondrial health, reduced senescence, and rescued bone formation. Conversely, Pink1 deficiency in BMSCs was sufficient to induce osteoporosis. Mechanistically, we identified that the mitochondrial ferritin FTMT is upregulated under iron-loading conditions and binds to PINK1, suppressing its phosphorylation and thereby preventing mitophagy initiation. This pathway is clinically relevant, as BMSCs from osteoporotic patients with high ferritin levels showed elevated FTMT and reduced PINK1 phosphorylation. Therefore, we identify a novel pathway in which FTMT-mediated disruption of mitophagy drives iron-induced osteoporosis. Our findings highlight mitophagy activation as a therapeutic strategy to prevent and treat bone loss under iron accumulation.
    Keywords:  Bone marrow mesenchymal stem cells; Iron accumulation; Mitochondrial ferritin; Mitophagy; Osteoporosis
    DOI:  https://doi.org/10.1016/j.redox.2026.104157
  5. Nat Commun. 2026 Apr 14.
    Mitophagy promotes lung repair and regeneration by restoring epithelial metabolic fitness.
    Pei Wu, Jiawei Chen, Li Liu, Ping Wang, Tiantian Lu, Shengxi Shen, Yiyuan Cao, Yuandong Sui, Run Liu, Xiajuan Huan, Ning Ding, Ying Xi.
      Alveolar Type II cells (AT2s) are the stem cells responsible for both lung homeostasis and regeneration. Mitochondrial dysfunction in AT2 cells has been implicated in both chronic and acute injury-induced alveolar diseases, including idiopathic pulmonary fibrosis (IPF) and viral pneumonia. However, the role of mitochondrial homeostasis in post-injury lung repair and regeneration remains elusive. Here we demonstrate that genetic depletion of Ubiquitin Specific Peptidase 30 (USP30), a negative regulator of mitophagy, boosts mitophagy and restores mitochondrial function in AT2 cells, leading to protection from injury-induced apoptosis and enhanced stem cell activity. Both global and AT2-specific Usp30 knockout (KO) promote alveolar regeneration, protecting the mice from bleomycin-induced lung fibrosis and influenza pneumonia. Moreover, pharmacological inhibition of USP30 effectively alleviates these conditions. Together, our findings reveal a previously underappreciated role for mitophagy in lung injury and repair and highlight USP30 inhibition as a promising therapeutic strategy for treating alveolar diseases.
    DOI:  https://doi.org/10.1038/s41467-026-71728-x
  6. Nat Commun. 2026 Apr 17.
    Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.
    Yunjuan Nie, Li Xu, Yanyan Liu, Jiao Li, Zhixu Wang, Xiaorun Zhai, Xiaoru Sun, Chunxiao Hu, Bo Xu, Yaxian Wu, Haitao Yu, Manjula Karpurapu, Huaqi Guo, Gaoshang Chai.
      Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease where macrophages drive fibrogenesis, yet Hdac11's role is unclear. We first identify pronounced Hdac11 upregulation in IPF lungs, which is associated with an enrichment in alveolar macrophages (AMs). Genetic ablation of Hdac11 or adoptive transfer of Hdac11-deficient macrophages markedly attenuates fibrosis. Specifically, Hdac11 deficiency significantly reduces M2 macrophage polarization in vivo and vitro and is associated with reduced macrophage-myofibroblast transition (MMT) like phenotypic reprogramming, thereby decreasing myofibroblast accumulation and profibrotic gene expression. Mechanistically, impaired mitophagy mediates Hdac11-mediated M2 macrophage polarization and is associated with MMT-like changes. Hdac11 regulates mitochondrial quality control by deacetylating Parkin at lysine 76, promoting its ubiquitination and degradation, which impairs mitophagy and drives profibrotic macrophage activation. Pharmacological Hdac11 inhibition effectively reverses bleomycin-induced fibrosis. Taken together, our work identifies Hdac11 as a target of Parkin-mediated mitophagy in macrophages, establishing Hdac11-Parkin axis disruption as an important mechanism in IPF and highlighting Hdac11 inhibition as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41467-026-71639-x
  7. Nat Commun. 2026 Apr 15.
    Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from parkinsonism to perinatal lethality.
    PSMF1 Study Group
      Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here we identify PSMF1 as a gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 18 pedigrees with 25 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/hPI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants may affect proteasomal abundance and assembly, and are associated with alterations of mitochondrial membrane potential, respiration, dynamics and mitophagy in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PI31 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1/hPI31 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as pathogenic contributors.
    DOI:  https://doi.org/10.1038/s41467-026-71351-w
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