bims-tofagi 2026-07-05 papers

Issue of 2026–07–05
ten papers selected by
Michele Frison, University of Cambridge

Elife. 2026 Jul 01. pii: e82205. [Epub ahead of print]15

Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation.

Priyanka Gajwani, Li Wang, Koushik Debnath, Pierina Danos, Young-Mee Kim, Shubhi Srivastava, Zijing Ye, Sarah Krantz, Dongmei Wang, Chinnaswamy Tiruppathi, Peter T Toth, Sriram Ravindran, Jalees Rehman.

Eukaryotic mitochondria are characterized by several features that represent vestiges of their prokaryotic ancestry. One such feature is the N-terminal formylation of proteins encoded by mitochondrial DNA that undergo translation by mitochondrial ribosomes. N-formylated proteins are also released by bacteria and trigger activation of immune cells such as neutrophils. Growing evidence indicates that circulating levels of mitochondrial formyl proteins are elevated in the serum of patients with excessive inflammatory responses. However, the mechanisms by which they are released into circulation are not known. In this study, we have identified vascular endothelial cells as a source of Pink1-dependent release of mitochondrial formyl proteins in response to inflammatory mediators. Mechanistically, the mitophagy mediator Pink1 is stabilized by inflammatory activation of endothelial cells, promoting mitophagy and mitochondrial formyl peptide release both in mice and primary human endothelial cells. Using nanoparticle delivery of Pink1-targeting sgRNA in mice expressing endothelial-specific Cas9, we developed a mouse model in which Pink1 is specifically depleted in the endothelium. Deletion of endothelial Pink1 decreased circulating formyl peptide levels, lowered lung neutrophil infiltration and reduced mortality in mice. We thus propose that endothelial cells upregulate pro-inflammatory mitophagy in response to inflammation, leading to the release of mitochondrial formyl peptides and detrimental neutrophil recruitment into the lung.

Keywords: cell biology; human; immunology; inflammation; mouse

DOI: https://doi.org/10.7554/eLife.82205

Metabolism. 2026 Jul 01. pii: S0026-0495(26)00196-4. [Epub ahead of print]183 156685

A thermosensitive TET-Parkin epigenetic axis couples mitochondrial quality control to adaptive thermogenesis in adipose tissue.

Seongjun Byun, Chan Hyeong Lee, Kyumin Jang, Minwoo Pak, Hyun-Ji Lee, Seongryeol Ryu, Inkyung Jung, Jungeun An, Myunggon Ko.

Adipose tissue thermogenesis is a major determinant of energy homeostasis, and its dysregulation contributes to obesity and metabolic disease. Parkin-mediated mitophagy is required for thermogenic adaptation, but the upstream mechanisms linking thermal cues to this pathway remain poorly defined. Here, we identify the ten-eleven translocation (TET) family of DNA dioxygenases as thermosensitive epigenetic regulators of Prkn transcription in adipocytes. Cold exposure coordinately suppressed TET expression and reduced global 5-hydroxymethylcytosine (5hmC) levels in white and brown adipose tissue through β-adrenergic signaling. Adipose-specific TET triple-knockout mice exhibited enhanced white fat beiging, brown fat activation, increased energy expenditure, and improved cold tolerance. Transcriptomic network analysis identified Parkin as a key mitophagy node in TET-deficient adipose tissue. Consistent with this, loss of adipose TET reduced Parkin expression, impaired mitophagic flux, and promoted accumulation of metabolically active mitochondria with increased respiratory capacity. Mechanistically, TET proteins occupied the Prkn promoter and maintained a transcriptionally permissive state through catalytic conversion of 5-methylcytosine to 5hmC, whereas TET loss increased promoter methylation and suppressed Prkn expression. Re-expression of wild-type, but not catalytically inactive, Parkin largely normalized mitochondrial content and respiratory activity in TET-deficient adipocytes. Together, these findings define a thermosensitive TET-Parkin epigenetic axis that links environmental cold signals to mitochondrial quality control during adaptive thermogenesis.

Keywords: Adaptive thermogenesis; Adipose tissue browning; Epigenetic regulation; Mitophagy; Parkin; TET dioxygenase

DOI: https://doi.org/10.1016/j.metabol.2026.156685

Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2521642123

Tau protein as a regulator of mitochondrial function and dynamics.

Eleni Tsakiri, Carlos Campos-Marques, Christina Ploumi, Kalliopi Skourti, Antonis Roussos, Eirini Mytilinaiou, Anastasia Vamvaka Iakovou, Ildete Luísa Ferreira, Chrysoula Dioli, Despoina D Gianniou, Martina Samiotaki, Jonas Campos, Clarissa Waites, Nuno Sousa, Ioannis P Trougakos, Joana M Silva, A Cristina Rego, Ioannis Sotiropoulos, Konstantinos Palikaras.

Mitochondrial damage is a shared hallmark of brain aging and neurodegeneration. While pathological Tau mutations disrupt mitochondrial dynamics and function, the physiological role of wild-type (WT) Tau in the maintenance of mitochondrial homeostasis remains poorly understood. Here, using Caenorhabditis elegans and mice lacking PTL-1, the nematode Tau-like homolog, and Tau respectively, we demonstrate that Tau deficiency promotes a shift toward a pro-fusion mitochondrial state associated with enhanced mitochondrial function and stress resistance. In both models, loss of Tau leads to increased mitochondrial activity and altered redox homeostasis, while it enhances resistance to heat and mitochondrial stress in C. elegans. Strikingly, loss of FZO-1, the mitofusin homolog, abolishes the beneficial phenotypes, whereas its overexpression phenocopies key aspects of Tau/PTL-1 deficiency. Together, our findings uncover a conserved role for WT Tau in restraining mitochondrial fusion and functional adaptation, highlighting its contribution to mitochondrial homeostasis and cellular stress responses.

Keywords: Tau; mitochondria; mitochondrial dynamics; neurodegeneration; neuron

DOI: https://doi.org/10.1073/pnas.2521642123

Autophagy. 2026 Jul 02.

Tegument protein UL16 of herpes simplex virus 1 suppresses the innate immune response by downregulating MAVS abundance via mitophagy.

Jingwen Wang, Rongli Zhu, Ping Yi, Mengyao Gan, Feng Long.

Herpes simplex virus 1 (HSV-1) is a globally prevalent pathogen that poses a significant health threat due to its lifelong latency. This persistence is driven by intricate immune evasion mechanisms, the deciphering of which remains a challenge. Here, we identified the HSV-1 tegument protein UL16 as a novel viral immunosuppressive factor, which significantly suppresses the RIGI-like receptor (RLR)-mediated antiviral immunity. We found that UL16 can interact with MAVS (mitochondrial antiviral signaling protein) and induce its degradation, thereby inhibiting type I interferon (IFN-I) production. Further investigation revealed that UL16-induced MAVS degradation was facilitated via mitophagy involving the mitochondrial cargo receptor FUNDC1 (FUN14 domain containing 1). Knockout of FUNDC1 expression completely disrupted UL16-induced MAVS degradation and restricted HSV-1 replication. In contrast, overexpression of FUNDC1 augmented the suppressive effect of UL16 on MAVS-triggered IFN-I signaling and consequently benefited viral replication. Notably, the C-terminal domain (CTD) of UL16 primarily accounted for its immunosuppressive function, which was also demonstrated to be essential for UL16 engagement with MAVS, FUNDC1 and MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). A conserved LC3-interacting region (LIR) motif within the UL16 CTD was identified to play a critical role in LC3 recruitment enhancement. Furthermore, the UL16-deficient HSV-1 exhibited markedly attenuated viral infectivity and pathogenicity in vivo. In summary, our findings uncover a previously uncharacterized pathway through which HSV-1 UL16 subverts host immunity by inducing mitophagy. This study provides critical insights into host-pathogen interactions and establishes a rational foundation for developing novel therapeutics against HSV-1 infection.Abbreviations:3-MA: 3-methyladenine; BNIP3L/NIX: BCL2 interacting protein 3 like; BSA: bovine serum albumin; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CARD: caspase recruitment domain; Cas9: CRISPR-associated system 9; CGAS: cyclic GMP-AMP synthase; co-IP: co-immunoprecipitation; COX8: cytochrome c oxidase subunit 8; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; CTD: C-terminal domain; Ctrl: control; CXCL10: C-X-C motif chemokine ligand 10; DAPI: 4,'6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; ds: double-stranded; FBS: fetal bovine serum; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK: human embryonic kidney; HSV-1: herpes simplex virus 1; IAV: influenza A virus; IFIH1/MDA5: interferon induced with helicase C domain 1; IFIT1/ISG56: interferon induced protein with tetratricopeptide repeats 1; IFN-I: type I interferon; IgG: Immunoglobulin G; IRF3: interferon regulatory factor 3; ISGs: IFN-stimulated genes; kDa: kilodalton; KO: knockout; KSHV: Kaposi sarcoma-associated herpesvirus; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MG132: cbz-leu-leu-leucinal; MOI: multiplicity of infection; NanoBiT: NanoLuc Binary Technology; NC: negative control; NTD: N-terminal domain; OPTN: optineurin; p-: phosphorylated; PFU: plaque-forming unit; PINK1: PTEN induced kinase 1; poly(I:C): polyinosinic-polycytidylic acid; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; qPCR: quantitative polymerase chain reaction; RIGI/RIG-I: RNA sensor RIG-I; RLR: RIGI-like receptor; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SeV: Sendai virus; sgRNA: single guide RNA; shRNA: short hairpin RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TM: transmembrane; TOMM20: translocase of outer mitochondrial membrane 20; TRAF: TNF receptor associated factor; TUFM: Tu translation elongation factor, mitochondrial; UL16: unique long region 16; VSV: vesicular stomatitis virus; VZV: varicella zoster virus; WCL: whole-cell lysate; WT: wild-type; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone.

Keywords: FUNDC1; HSV-1; MAVS; UL16; mitophagy

DOI: https://doi.org/10.1080/15548627.2026.2698747

Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00075-9. [Epub ahead of print]91 102185

DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.

Melissa Geng, Dahai Wang, Sam Kavoosi, Brett A Kaufman, Neal Sondheimer.

Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.

Keywords: Autophagy; Guanine quadruplex; Heteroplasmy shifting; Mitochondrial fission; Mitochondrial heteroplasmy

DOI: https://doi.org/10.1016/j.mito.2026.102185

Commun Biol. 2026 Jul 03.

Non-canonical role of Ku80 stabilizes Rab7A to enhance mitolysosome formation and chemotherapy in liver cancer.

Baojia Zou, Lukun Yang, Yihua Dai, Peiping Li, Manyao Zhang, Bailiang He, Jianzhong He, Decheng Li, En Lin, Chaonong Cai, Yiguang Lin, Mingjian Lu, Jian Li.

Targeting mitophagy is a potential strategy to tackle chemoresistance and improve chemotherapy in cancer. Ku80 is reported to play a role in chemoresistance and could exert non-canonical functions in mitophagy, but the mechanism remains largely unknown. Here, we report that increased expression of Ku80 leads to prominent mitophagy in liver cancer cells and tissues. Mechanistically, Ku80 directly regulates Rab7A to enhance formation of mitolysosomes. Elevated cytoplasmic levels of Ku80 and Rab7A in liver cancer tissues correlate with improved disease-free survival (DFS) and overall survival (OS) and significantly enhance the efficacy of adjuvant chemotherapy in surgical liver cancer patients. Several FDA-approved drugs can be repurposed as mitophagy activators, which enhance the chemotherapeutic agent epirubicin and Ku80/Rab7A interactions. Therefore, we have discovered the non-canonical role of Ku80 in mitophagy by directly regulating Rab7A in liver cancer, which is a potentially druggable and molecular subtyping strategy to improve chemotherapy outcomes.

DOI: https://doi.org/10.1038/s42003-026-10554-9

Nat Metab. 2026 Jun 29.

Mitochondrial quality control in human ageing and longevity.

Anna Picca, Luigi Ferrucci.

Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.

DOI: https://doi.org/10.1038/s42255-026-01563-3

Mol Neurobiol. 2026 Jul 02. pii: 738. [Epub ahead of print]63(1):

Nrf2 Activators in Parkinson's Disease: Modulating Mitophagy and Regulating Cuproptosis.

Junjing Xu, Jiawei Xiang, Yong Zhang, Xuehong Liu.

Parkinson's disease (PD), one of the most prevalent age-related neurodegenerative disorders, is neuropathologically defined by the progressive degeneration and massive loss of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. Multiple pathological cascades, which include excessive oxidative stress, persistent neuroinflammation, aberrant cuproptosis, and mitochondrial dysfunction, converge to drive PD pathogenesis and aggravate its progression. Nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal transcription factor governing antioxidant defense and cellular stress responses, is markedly downregulated and functionally compromised within the pathological microenvironment of PD-affected brain tissue. A growing body of evidence has demonstrated that Nrf2 activators represent promising and innovative therapeutic candidates for the treatment of PD. These compounds effectively trigger the activation of the downstream Nrf2 signaling cascade, thereby promoting the initiation and execution of mitophagy to eliminate dysfunctional and damaged mitochondria and restore intracellular metabolism homeostasis. Meanwhile, activation of the Nrf2 signaling pathway suppresses aberrant intracellular copper accumulation and prevents excessive lipid peroxidation, thereby exerting a robust inhibitory effect on neuronal cuproptosis. This review systematically delineates the regulatory mechanisms by which Nrf2 activators modulate pivotal molecular-level biological processes. It further synthesizes and critically appraises the most recent preclinical findings as well as emerging early-stage clinical data regarding Nrf2-targeted therapeutic strategies for PD, while also delineating prevailing challenges and outlining prospective avenues for future investigation in this domain. Collectively, targeting the Nrf2 signaling pathway constitutes a promising integrative therapeutic strategy for the management of PD.

Keywords: Cuproptosis; Mitophagy; Neuroprotection; Nrf2 activators; Nrf2 signaling pathway; Parkinson’s disease

DOI: https://doi.org/10.1007/s12035-026-06036-y

J Biochem. 2026 Jun 30. pii: mvag048. [Epub ahead of print]

BNIP3/NIX-dependent mitophagy: molecular mechanisms and physiological roles.

Tamara Ginevskaia, Takayuki Mito, Keiichi Inoue, Tomotake Kanki.

Mitochondria are essential for cellular metabolism and homeostasis, and their quality and quantity must therefore be tightly controlled. Mitophagy, a selective form of autophagy targeting mitochondria, contributes to this control by eliminating damaged or superfluous mitochondria. Among the known mitophagy pathways, BNIP3/NIX-dependent mitophagy has emerged as a key mechanism, particularly under hypoxic and metabolic stress. Recent studies have provided important insights into how BNIP3 and NIX are transcriptionally induced, post-translationally regulated, and functionally coupled to the core autophagy machinery. These studies have also clarified their roles in isolation membrane tethering, membrane elongation, and mitophagosome formation. Beyond its molecular basis, accumulating evidence indicates that BNIP3/NIX-dependent mitophagy contributes to mitochondrial homeostasis, redox balance, and cellular stress adaptation. This review summarizes recent progress in understanding the molecular mechanisms and physiological significance of BNIP3/NIX-dependent mitophagy.

DOI: https://doi.org/10.1093/jb/mvag048

iScience. 2026 Jul 17. 29(7): 116449

Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.

Enming Qiu, Guoqing Lv, Jianing Hou, Zhou Li, Gang Wang.

Mitophagy is a selective autophagy that degrades dysfunctional mitochondria to maintain cellular homeostasis. Mitophagy is functionally coordinated with and regulated by mitochondrial biogenesis and mitochondrial dynamics, which include mitochondrial fusion, mitochondrial fission, and mitochondrial trafficking. Furthermore, researches have demonstrated that mitophagy plays a critical role in the occurrence and development of digestive cancer. Nonetheless, the mechanism of how mitophagy modulates digestive cancer and the mechanism of how mitochondrial biogenesis and dynamics influence mitophagy warrant more investigations. This review summarizes the current understanding of the regulatory mechanism of mitophagy and outlines recent advances from investigations that explore how mitochondrial biogenesis and dynamics coordinate with mitophagy. Additionally, this review provides a comprehensive view about how mitophagy could regulate the occurrence and development of digestive cancer. A deeper understanding about the role of mitophagy in regulation of digestive cancer benefits the development of more efficient therapeutic strategies for patients.

Keywords: Biological sciences

DOI: https://doi.org/10.1016/j.isci.2026.116449