bims-tofagi Biomed News
on Mitophagy
Issue of 2026–10–18
eight papers selected by
Michele Frison, University of Cambridge
  1. Innate immune signaling relays environmental cues to mitophagy for metabolic adaptation to obesity.
  2. Local ROS and inefficient autophagosome formation limit Optineurin-mediated mitophagy in neurons.
  3. Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia.
  4. PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy.
  5. Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.
  6. Selective autophagy pathways in ageing and neurodegeneration: Emerging roles for mitophagy and nucleophagy.
  7. Topical application of urolithin A activates mitophagy and enhances mitochondrial function to promote skin longevity.
  8. After delivery: How recipient cells shape the fate and function of transplanted mitochondria.
  1. Autophagy. 2026 Oct 13. 1-3
    Innate immune signaling relays environmental cues to mitophagy for metabolic adaptation to obesity.
    Courtney J Campbell, Scott A Soleimanpour.
      The mechanisms by which pancreatic β cells sense and communicate environmental cues to mitochondria to maintain insulin secretion remain poorly understood. We identified that β cells transduce metabolic stress, such as during obesity or glucolipotoxicity, through the innate immune signaling adaptor TRAF6 to regulate mitochondrial quality control. TRAF6 was dispensable for β-cell function at baseline yet was essential for glucose-stimulated insulin secretion in mouse or human β cells following nutrient excess. TRAF6 was required for the recruitment of components of both ubiquitin- and receptor-mediated mitophagy pathways to clear dysfunctional mitochondria following metabolic stress. Interestingly, concomitant loss of the ubiquitin-mediated mitophagy effector Parkin restored glucose homeostasis and mitophagy flux in TRAF6-deficient β cells by relieving impediments in receptor-mediated mitophagy. Together, we found that TRAF6 forms a molecular relay linking environmental signals to multiple mitophagy pathways to equip β cells with the means to adapt to metabolic demand and prevent diabetes.Abbreviations: ADP: adenosine diphosphate; ATP: adenosine triphosphate; BNIP3: BCL2 interacting protein 3; GSIS: glucose-stimulated insulin secretion; HFD: high-fat diet; MFN2: mitofusin 2; PRKN: parkin RBR E3 ubiquitin protein ligase; RNF41/NRDP1: ring finger protein 41; SQSTM1/p62: sequestosome 1; T2D: type 2 diabetes; TAX1BP1: Tax1 binding protein 1; TLR: Toll-like receptor; TRAF6: TNF receptor associated factor 6.
    Keywords:  Autophagy; beta cell; innate immunity; mitochondria; parkin; traf6
    DOI:  https://doi.org/10.1080/15548627.2026.2747028
  2. bioRxiv. 2026 Oct 03. pii: 2026.01.16.700014. [Epub ahead of print]
    Local ROS and inefficient autophagosome formation limit Optineurin-mediated mitophagy in neurons.
    Jordan R Green, Anne E Ojo, Molly K Gooden, Lillian D Papell, Titilola D Kalejaiye, Chantell S Evans.
      Mitophagy is a quality control mechanism that maintains neuronal health by removing damaged mitochondria. In neurons, mitophagy can be driven by Optineurin (OPTN), a selective autophagy receptor recruited in response to oxidative stress. However, mechanistic studies of mitophagy have relied mainly on non-neuronal cell lines and acute damage paradigms. It remains unknown whether these findings translate to neurons under physiological stress conditions. Here, we investigated the temporal dynamics of OPTN-dependent mitophagy under mild oxidative stress using live-cell imaging in primary rat hippocampal neurons. We found that autophagosomes failed to readily engulf OPTN-positive (OPTN+) mitochondria, revealing a previously unidentified rate-limiting step in neuronal OPTN-mediated mitophagy. Additionally, OPTN+ mitochondria colocalized with acidified lysosomes over timescales significantly longer than previously reported. These OPTN+ mitochondria displayed locally elevated reactive oxygen species (ROS). Scavenging mitochondrial ROS increased lysosomal colocalization with damaged mitochondria and accelerated mitophagy progression. Together, these findings indicate that redox signaling contributes to the slow timescale of OPTN-mediated mitophagy in neurons.
    DOI:  https://doi.org/10.64898/2026.01.16.700014
  3. Leukemia. 2026 Oct 13.
    Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia.
    Romain Vazquez, Maxime Sajot, Jad Nasrallah, Rudy Birsen, Ismaël Boussaid, Morgane Plevenage, Zubaidan Tuerdi, Axelle Guedon, Lilia Cantero Aguilar, Tony Huynh, Natacha Johnson, Chloé Friedrich, Eric Grignano, Justine Decroocq, Lise Willems, Carole Almire, Marie-Clotilde Alves-Guerra, Evelyne Lauret, Yannick Simoni, Michaela Fontenay, Olivier Kosmider, Didier Bouscary, Clement Larrue, Nicolas Chapuis.
      Acute myeloid leukemia (AML) cells are highly dependent on mitochondrial activity for survival, with this metabolic reliance driven in part by BCL-2, which is therapeutically targeted by venetoclax-based therapies. The regulation of mitochondrial dynamics in leukemic cells is therefore essential for maintaining mitochondrial homeostasis. However, the mechanisms that enable selective degradation of damaged mitochondria (mitophagy) are still poorly understood in AML. In this study, we sought to elucidate the role of PTEN-induced putative kinase 1 (PINK1), a key sensor of mitochondrial stress, in regulating mitophagy in leukemic cells. Our results identified PINK1 as a central modulator of mitophagy. Genetic depletion of PINK1 reduced both basal and stress-induced mitophagy, leading to mitochondria accumulation and functional impairment. Additionally, we discovered that PINK1 stabilization during mitochondrial stress is regulated by Prohibitin 2 (PHB2), and that depletion or inhibition of PHB2 mirrored the biological effects of PINK1 loss. Notably, both genetic depletion of PINK1 or PHB2, as well as pharmacological inhibition of PHB2, significantly increased AML cell sensitivity to venetoclax both in vitro and in vivo. Together, these findings highlight the potential of targeting the PHB2/PINK1 signalling pathway to improve the efficacy of venetoclax-based therapies in AML by disrupting the mitophagy process.
    DOI:  https://doi.org/10.1038/s41375-026-03160-5
  4. Sci Adv. 2026 Oct 16. 12(42): eaef8820
    PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy.
    Diogo Gonçalves, Emma Guilbaud, Léa Di Mascio, Camille Guerrier, Linda Mejri, Sonia Núñez-Vázquez, Lucie Levasseur, Rachel Paul, Corinne Menigot, Christophe Bontoux, Guylène Rignol, Véronique Hofman, Paul Hofman, Marin Truchi, Bernard Mari, Laurent Yvan-Charvet, Johanna Chiche, Sandrine Marchetti, Jean-Ehrland Ricci.
      Mitophagy, the selective degradation of mitochondria by lysosomes, is a major mitochondrial quality-control pathway, yet its role in lung cancer initiation and therapeutic response remains poorly understood. We investigated PINK1-dependent mitophagy in human lung adenocarcinoma and directly monitored mitophagy in vivo using mito-QC reporter mice during lung tumor development. We found that PINK1 activity and mitophagy are increased in human tumors and are activated from the earliest stages of tumorigenesis. Genetic inhibition of PINK1 impaired oncogenic transformation but had little impact once tumor cells were established, identifying mitophagy as a critical early adaptation during lung cancer initiation. PINK1 deficiency markedly enhanced the efficacy of KRAS-targeted therapy in vitro and in vivo. Together, our findings identify PINK1-dependent mitophagy as an early vulnerability in KRAS-driven lung cancer and provide a rationale for targeting mitophagy to improve the efficacy of KRAS-targeted therapies.
    DOI:  https://doi.org/10.1126/sciadv.aef8820
  5. J Inherit Metab Dis. 2026 Nov;49(6): e70259
    Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.
    Marianna Maddaluno, Laura Cinque, Viviana Cetrangolo, Chiara De Leonibus.
      Selective autophagy is increasingly recognized as a fundamental quality-control mechanism that complements bulk autophagy by enabling the targeted degradation of specific intracellular cargos, including mitochondria, endoplasmic reticulum (ER), lipid droplets, glycogen, peroxisomes, ferritin, ribosomes, and protein aggregates. Cargo selectivity is mediated by selective autophagy receptors (SARs), which link damaged or superfluous substrates to the autophagic machinery through LC3/GABARAP interactions, thereby coordinating cargo sequestration. Recent studies have revealed substantial mechanistic differences between bulk and selective autophagy, highlighting the specialized signaling pathways, receptor networks, and transcriptional programs that regulate selective cargo clearance. Dysregulation of these pathways has emerged as a key contributor to the pathogenesis of inherited metabolic diseases (IMDs), a heterogeneous group of genetic disorders characterized by defective metabolism and multisystem involvement. This review summarizes the molecular mechanisms underlying major forms of selective autophagy, including mitophagy, pexophagy, glycophagy, lipophagy, ER-phagy, and ferritinophagy. It also discusses their relevance across IMD classes, such as mitochondrial disorders, lysosomal storage disorders, and peroxisomal diseases, among many others. Furthermore, selective autophagy is highlighted as a potential therapeutic target, with modulation of autophagy receptors and signaling pathways offering promising strategies to restore cellular homeostasis and improve disease manifestations in IMDs.
    Keywords:  bulk autophagy; inherited metabolic diseases (IMDs); selective autophagy; selective autophagy cargos (SACs); selective autophagy receptors (SARs)
    DOI:  https://doi.org/10.1002/jimd.70259
  6. FEBS J. 2026 Oct 13.
    Selective autophagy pathways in ageing and neurodegeneration: Emerging roles for mitophagy and nucleophagy.
    Maria Markaki, Nektarios Tavernarakis.
      Ageing is characterized by the progressive accumulation of molecular and cellular damage, driven by both genetic and nongenetic factors and ultimately leading to functional decline and an increased risk of disease. Convergent evidence indicates that many of the mechanisms influencing ageing are intimately related to the ability of the organism to cope with intrinsic and extrinsic stress. Key determinants of this capacity are the molecular pathways that coordinate stress responses throughout life. Among these, general and cargo-specific autophagy have emerged as integral components of cellular and systemic adaptation to stress. Here, we focus on mitophagy, a selective form of autophagy targeting mitochondria, and nucleophagy, the selective autophagic recycling of nuclear material. These processes help safeguard the integrity of two organelles that are central to long-term cellular survival and function. Such homeostatic mechanisms are vital in long-lived neurons, where they mediate damage removal during ageing to protect against neurodegeneration. We further discuss how perturbations in these autophagic pathways may contribute to ageing and neurodegenerative disorders. Finally, we outline key open questions and future challenges in the field, including the largely unexplored possibility of functional connections between mitophagy and nucleophagy, which we identify as an important direction for future research.
    Keywords:  ageing; autophagic pathways; homeostasis; mitophagy; neurodegeneration; nucleophagy; organelle quality control
    DOI:  https://doi.org/10.1111/febs.70738
  7. iScience. 2026 Oct 16. 29(10): 117646
    Topical application of urolithin A activates mitophagy and enhances mitochondrial function to promote skin longevity.
    Davide D'Amico, Julie Faitg, Frédéric Amaral, Carine Ballihaut, Andréane M Fouassier, Charlotte Tissot, Isha Rana, Julien Laboureau, Natascha Hennighausen, Marianne Brandt, Nicholas Kron, Xavier Marat, Chantal Jouy, Annie F Black, Gayané Azadiguian, Delphine Guillon, Jean-Thierry Simonnet, Chris Rinsch, Anurag Singh.
      Urolithin A (UA, Mitopure), a postbiotic that promotes mitophagy and mitochondrial function following oral administration, was evaluated for its effects on skin health in human skin models and when applied topically to healthy subjects in randomized clinical studies. UA tested in 2D and 3D reconstructed human skin and ex vivo human skin explants showed enhanced mitochondrial respiration, activated mitophagy markers, reduced inflammatory mediators and senescence-associated markers, and increased proteins involved in extracellular matrix structure and epidermal differentiation. Safety was confirmed in a human repeat-insult patch test. In randomized, placebo-controlled clinical studies, UA reduced periorbital wrinkle depth after 8 weeks and attenuated UVB-induced erythema. Skin transcriptomics supported increased extracellular matrix and epidermal development programs together with decreased inflammatory and senescence-associated signaling. These findings indicate that topical UA engages cellular pathways associated with skin resilience to promote skin health and longevity.
    Keywords:  Ki-67; collagen III; collagen VII; elastin; filaggrin; inflammation; mitochondria; mitophagy; skin aging; urolithin A
    DOI:  https://doi.org/10.1016/j.isci.2026.117646
  8. Clin Transl Med. 2026 Oct;16(10): e70857
    After delivery: How recipient cells shape the fate and function of transplanted mitochondria.
    Zhi-Yuan Zhang, Bo-Quan Qin, Shi-Zhou Wu, Hui Zhang.
       BACKGROUND: Mitochondrial transplantation is built on a simple idea: failing cells might be rescued by healthy mitochondria. The approach has entered early clinical testing, and encapsulation and cell-type targeting have improved uptake in selected systems. Better delivery, however, does not explain the therapy.
    MAIN BODY: Internalised donor mitochondria encounter an established network, quality-control machinery and sensors for mitochondrial material. Donor material may remain in the endolysosomal system or reach the cytosol. Cytosolic fates include network integration, clearance and a candidate functional contribution without fusion. Intracellular processing may also generate bioactive cargo. These fates imply different mechanisms and evidence requirements. This Review examines how recipient cells shape the contribution of internalised mitochondria, while recognising extracellular routes to benefit. We distinguish direct transplantation evidence from mechanistic support drawn from endogenous mitochondrial biology and natural intercellular transfer. The required donor fate and duration depend on the therapeutic task. Transient rescue may rely on short-term donor function or productive processing in specific models; sustained support may depend on continued donor function, recipient adaptation or redosing. Durable mitochondrial DNA (mtDNA) correction requires donor-mtDNA retention and replication.
    CONCLUSIONS: Linking these tasks to product design, safety assessment and clinical endpoints shifts the question from how many mitochondria enter cells to what they accomplish after arrival.
    KEY POINTS: Recipient-cell handling shapes what transplanted mitochondria do after uptake. Uptake, structural integration and donor mitochondrial DNA retention require distinct evidence. Transient rescue, sustained support and durable mitochondrial DNA correction impose different requirements. Therapeutic goals should guide donor selection, product testing and clinical endpoints.
    Keywords:  endosomal escape; heteroplasmy; innate immunity; mitochondrial fusion; mitochondrial transplantation; mitophagy; translational medicine
    DOI:  https://doi.org/10.1002/ctm2.70857
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