bims-tofagi 2026-03-08 papers

Issue of 2026–03–08
six papers selected by
Michele Frison, University of Cambridge

Autophagy Rep. 2026 ;5(1): 2635914

Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.

Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Nobuo N Noda, Tomotake Kanki.

Mitophagy selectively eliminates damaged or excess mitochondria to maintain mitochondrial homeostasis. During this process, mitochondria need to be fragmented to allow their sequestration within autophagosomes. However, the well-known dynamin-related fission factors, Dnm1 in yeasts and DNM1L/DRP1 in mammals, are dispensable for mitophagy, leaving the underlying mechanism unresolved. In the yeast Saccharomyces cerevisiae, the identification of the mitochondrial intermembrane space protein Atg44 (autophagy-related 44) uncovered the existence of a new class of proteins, mitofissin, involved in mitochondrial fission during mitophagy. Whether Atg44 alone is sufficient for mitophagy-associated fission remained unclear. Our recent study identified Mfi2 (mitofissin 2) as a mitochondrial outer membrane-resident mitofissin that is required for efficient mitophagy and acts independently of Dnm1. Our findings indicate that mitophagy-associated mitochondrial fission is driven by mitofissins acting from both the inner and outer mitochondrial membranes. Here, we discuss remaining issues, including how mitofissin activities are regulated and how their function is modulated by mitochondrial lipids such as cardiolipin.

Keywords: Atg44; Dnm1; Mfi2; mitochondrial fission; mitofissin; mitophagy

DOI: https://doi.org/10.1080/27694127.2026.2635914

Mol Biol Cell. 2026 Mar 04. mbcE25110560

Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.

Yingying Sun, Xudong Fu, Yi Li, Mengfan Peng, Lei Yang.

Aging is a complex biological process that heightens susceptibility to age-related diseases, often driven by declining mitochondrial function. Mitophagy, the selective removal of damaged mitochondria, is a key quality-control mechanism essential for maintaining cellular health, and its decline has been closely linked to aging. However, the specific role of mitophagy in cellular senescence, a hallmark of aging, remains insufficiently understood, largely due to the lack of methods to manipulate mitophagy. In this study, we employed UMI-77, a new potent mitophagy activator, to evaluate its effects on senescence in mouse mesenchymal stem cells (MSCs). Our results show that UMI-77 preserves mitochondrial integrity and effectively delays cellular senescence through mitophagy. Mechanistically, UMI-77 markedly suppressed the senescence-associated secretory phenotype (SASP). Together, our findings reveal a new anti-aging therapeutic application for UMI-77 by targeting senescence-associated chronic inflammation through mitophagy induction and SASP reduction.

DOI: https://doi.org/10.1091/mbc.E25-11-0560

Acta Neuropathol. 2026 Mar 04. pii: 23. [Epub ahead of print]151(1):

Association of mitochondrial genetic background with pS65-Ub in Lewy body disease.

Ngan Le Kim Tran, Xu Hou, Michael G Heckman, Fabienne C Fiesel, Shunsuke Koga, Molly M Watkins, Hanna J Sledge, J Raphael Gibbs, Bryan J Traynor, Clifton L Dalgard, Sonja W Scholz, Dennis W Dickson, Wolfdieter Springer, Owen A Ross.

Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy is a mitochondrial quality-control pathway in which mitochondria tagged with ubiquitin phosphorylated at Serine 65 (pS65-Ub) are targeted for degradation via the autophagy-lysosome system. We previously identified a significant genome-wide association between apolipoprotein E ε4 [APOE ε4] with pS65-Ub levels in the hippocampus of Lewy body disease (LBD). However, the relationship between genetic background in the mitochondrial genome and the PINK1-PRKN pathway biomarker pS65-Ub remains to be elucidated. In this study, we examined whether mitochondrial DNA (mtDNA) variation contributes to changes in pS65-Ub level in 514 neuropathologically confirmed LBD brains, with replication in an independent cohort of 384 LBD brains. No individual mtDNA haplogroup was significantly associated with pS65-Ub levels after correction for multiple testing (P < 0.005 considered significant); mtDNA haplogroup V exhibited a nominally significant (P < 0.05) association, but this association was not observed in an independent replication series. Our data reveal an overall lack of direct evidence linking mtDNA variations to mitophagy marker pS65-Ub levels in LBD, suggesting that mitochondrial damage is unlikely to be explained by major mtDNA determinants alone and may instead reflect cumulative and multilayered perturbations of mitochondrial function. Single cell analyses combined with larger replication cohorts integrating multi-omics datasets will be essential to validate these findings and to advance the discovery of biomarkers for mitochondrial dysfunction in neurodegeneration.

Keywords: Lewy body disease; Mitochondrial haplogroup; Neuropathology; mtDNA

DOI: https://doi.org/10.1007/s00401-026-02993-9

J Diabetes. 2026 Mar;18(3): e70199

The Interaction Between Mitophagy Dysregulation and the Diabetic Bladder Microenvironment.

Shi Li, Zongyao Fan, Zheng Duan, Jun Xue, Zhongqing Wei.

Diabetic bladder dysfunction (DBD) is a prevalent and multifactorial urological complication of diabetes, with pathogenesis driven by complex interactions between hyperglycemia-induced oxidative stress, mitochondrial dysfunction, and bladder microenvironment dysregulation. Mitophagy, a selective autophagic process critical for mitochondrial quality control, has been linked to various metabolic diseases, but its precise role and the bidirectional interactions with the diabetic bladder microenvironment remain underexplored. This review outlines a novel, self-reinforcing feedback loop central to DBD progression. In this cycle, hyperglycemia impairs both the PINK1/Parkin-mediated mitophagy pathway and ubiquitin-independent pathways like FUNDC1 under hypoxic conditions, leading to the accumulation of damaged mitochondria. Mitochondrial dysfunction then exacerbates microenvironmental damage through excessive mitochondrial reactive oxygen species (mtROS) production, release of damage-associated molecular patterns (DAMPs), and activation of the NLRP3 inflammasome, which further drives inflammation, fibrosis, and extracellular matrix (ECM) remodeling. This aggravated microenvironment inhibits mitophagy, thereby accelerating the pathogenic cycle. Beyond elucidating this loop, this review suggests that targeting it offers a promising therapeutic strategy. A breakthrough in DBD treatment may necessitate a combined approach that both restores mitophagy and modulates the microenvironment. Additionally, this study critically reviews several promising, yet underexplored, interventions, including pharmacological mitophagy activation with urolithin A, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome inhibition via MCC950, and advanced techniques like nanoparticle-mediated PINK1 mRNA delivery and CRISPR/Cas9-based Parkin gene editing. Future research should incorporate spatial transcriptomics to resolve cellular heterogeneity, develop targeted nanodelivery systems, and establish mechanism-driven, highly specific combination therapies to enable precision medicine for DBD.

Keywords: DBD; PINK1/Parkin pathway; bladder microenvironment; mitophagy dysregulation; oxidative stress

DOI: https://doi.org/10.1111/1753-0407.70199

Autophagy. 2026 Mar 06.

Autocrine SFRP2 (secreted frizzled related protein 2) enhances lung myofibroblast fibrogenic activity by suppressing PINK1-mediated mitophagy initiation.

Yingying Lin, Tianxiang Lei, Yifan Jia, Meiling Yao, Xiaofeng Wang, Shaojie Huang, Zhongxing Wang, Xiaofan Lai.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease driven by persistent activation of pulmonary myofibroblasts, but the regulatory mechanisms sustaining this pathological state remain incompletely understood. Using single-cell RNA sequencing (scRNA-seq), we identified SFRP2 (secreted frizzled related protein 2) as a critical mediator of profibrotic myofibroblasts in IPF lungs. Functional studies revealed that SFRP2 acted in an autocrine manner to promote myofibroblast activation and extracellular matrix (ECM) production. Mechanistically, SFRP2 activated FZD5-mediated non-canonical WNT-Ca2 + signaling, leading to PPP3/calcineurin-dependent translocation of PINK1 from the outer to the inner mitochondrial membrane (IMM), where it was degraded, thereby inhibiting PINK1-mediated mitophagy. Furthermore, therapeutic intervention with AAV6-shSfrp2, SFRP2-neutralizing antibody, or the autophagy inducer rapamycin significantly ameliorated lung fibrosis in bleomycin (BLM)-induced mouse models. Our results define a novel autocrine SFRP2-mitophagy regulatory axis that perpetuates myofibroblast activation and represents a promising therapeutic target for pulmonary fibrosis.

Keywords: Extracellular matrix; PINK1-mediated mitophagy; WNT-Ca2 + signaling; idiopathic pulmonary fibrosis; mitochondrial reactive oxygen species; myofibroblast fibrogenic activity

DOI: https://doi.org/10.1080/15548627.2026.2642341

NPJ Aging. 2026 Mar 05.

Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.

Claudia Jara, Leslye Venegas-Zamora, Han S Park-Kang, Matías Lira, Micaela Ricca, Sebastian Valenzuela, Cheril Tapia-Rojas.

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.

DOI: https://doi.org/10.1038/s41514-026-00351-3