bims-tofagi Biomed News
on Mitophagy
Issue of 2026–03–01
seven papers selected by
Michele Frison, University of Cambridge
  1. Regulation of mitophagy by Fis1 and Fascin1-organized actin.
  2. The AAA-ATPase Yta4 inhibits the interaction between Ppa2 and Atg43 to promote Atg43 phosphorylation and mitophagy.
  3. Monitoring neuronal mitophagy and locomotion deficits in a C. elegans model of Alzheimer's disease.
  4. Recessive PPTC7 deficiency triggers excessive mitophagy to cause a severe inborn error of metabolism with hypomyelinating leukodystrophy.
  5. Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
  6. Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.
  7. Microautophagy: current understanding of its molecular mechanisms and functions.
  1. Curr Biol. 2026 Feb 24. pii: S0960-9822(26)00134-X. [Epub ahead of print]
    Regulation of mitophagy by Fis1 and Fascin1-organized actin.
    Shintaro Nakajima, Ting-Yu Wang, Tsui-Fen Chou, Yogaditya Chakrabarty, David C Chan.
      Mitophagy, the autophagic degradation of mitochondria, plays a central role in controlling the quality and quantity of mitochondria, thereby ensuring cellular health. The mitochondrial outer membrane protein Fis1 is important for several types of mitophagy, but its mechanism of action remains unclear. F-actin is recruited to autophagic cargo and is important for autophagic progression, but the mechanism for its recruitment is poorly understood. To address the molecular function of Fis1, we performed affinity purification of Fis1 and mass spectrometry and identified the actin-bundling protein Fascin1 as a physical interactor. We demonstrate that Fis1 is required for recruitment of Fascin1 as well as F-actin to mitochondria under stress conditions, including mitochondrial depolarization and iron chelation. Iron chelation also triggers mitophagy that is independent of the Parkinson's associated gene Parkin, and we show that Fis1 enables recruitment of Fascin1-organized F-actin to facilitate proper morphogenesis of autophagosomes and the ensuing mitochondrial degradation. In contrast, although Parkin-mediated mitophagy also relies on Fis1, it is unaffected by loss of Fascin1 or F-actin recruitment. These findings indicate that Fis1 has distinct modes of action in mitophagy, depending on the triggering cellular stress. They establish Fis1 as a key driver of Fascin1 and F-actin recruitment to mitochondria, events that are critical for autophagosome morphogenesis during iron-chelation-induced mitophagy.
    Keywords:  Fascin1; Fis1; actin; autophagy; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.cub.2026.01.062
  2. J Biol Chem. 2026 Feb 25. pii: S0021-9258(26)00196-1. [Epub ahead of print] 111326
    The AAA-ATPase Yta4 inhibits the interaction between Ppa2 and Atg43 to promote Atg43 phosphorylation and mitophagy.
    Ke Liu, Jiajia He, Yifan Wu, Chenhui Zhao, Shuaijie Yan, Fangyuan Xiong, Xing Liu, Xuebiao Yao, Chuanhai Fu.
      AAA-ATPase Yta4/Msp1/ATAD1 is a well-known quality control factor that clears mistargeted tail-anchored proteins and precursor proteins on mitochondria. However, whether Yta4 preserves mitochondrial homeostasis through alternate pathways remains unclear. Traditionally, mitophagy has been recognized as a crucial pathway for eliminating dysfunctional mitochondria, thereby ensuring the maintenance of mitochondrial homeostasis. In this study, we unveil a novel role for Yta4 in sustaining mitochondrial homeostasis by facilitating mitophagy in fission yeast. The absence of Yta4 delays the phosphorylation of the mitophagy receptor Atg43 and specifically inhibits mitophagy. Additionally, Atg43 phosphorylation sites Ser32, Ser35, and Ser36, which are crucial for mitophagy, were identified. We further found that the phosphatase Ppa2 plays a major role in Atg43 dephosphorylation and inhibits excessive mitophagy. Yta4 physically interacts with both Atg43 and Ppa2, and coordinates with Ppa2 to modulate Atg43 phosphorylation and mitophagy. Moreover, Yta4 and Ppa2 bind to the same cytosolic region of Atg43, and Yta4 inhibits the interaction between Atg43 and Ppa2. Collectively, our findings suggest that Yta4 promotes mitophagy by ensuring the effectiveness of Atg43 phosphorylation. Thus, our findings reveal the novel function of Yta4 in regulating mitophagy and expand the understanding of the molecular mechanisms underlying mitophagy in fission yeast.
    Keywords:  ATAD1; PP2A; fission yeast; mitochondria; phosphatase; phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2026.111326
  3. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00243-2. [Epub ahead of print]203 89-110
    Monitoring neuronal mitophagy and locomotion deficits in a C. elegans model of Alzheimer's disease.
    Giorgos Garcia Niforos, Eleni Tsakiri, Konstantinos Palikaras.
      Neurodegenerative diseases, such as Alzheimer's disease (AD), pose significant socioeconomic and personal burdens due to progressive cognitive and motor decline. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and tau tangles, alongside with emerging evidence linking metabolic dysfunction to its early disease pathogenesis. Impaired mitochondrial selective autophagy (known as mitophagy) and excessive mitochondrial dysfunction have been implicated as key contributors to disease progression. To uncover the mechanistic underpinnings of AD, Caenorhabditis elegans offers a powerful model system providing a fully mapped nervous system, transparency for live imaging, and evolutionary conserved pathways mirroring human pathophysiology. Here, we employ a pan-neuronal Aβ1-42 -expressing C. elegans strain to phenocopy early metabolic disturbances characteristic of AD. Our methodology integrates automated motility tracking with confocal microscopy, utilizing the mitochondria-targeted Rosella biosensor to assess mitophagy dynamics in vivo. This platform enables quantitative assessment of locomotion deficits and spatiotemporal monitoring of mitophagy alterations driven by Aβ1-42-induced toxicity. Our method provides a robust tool for screening genetic and pharmacological interventions aimed at mitigating AD-associated mitochondrial dysfunction and neurodegeneration.
    Keywords:  Alzheimer’s disease; Caenorhabditis elegans; Mitochondria; Mitophagy; Motility; Neurodegeneration; Neurons
    DOI:  https://doi.org/10.1016/bs.mcb.2025.12.001
  4. Res Sq. 2026 Feb 17. pii: rs.3.rs-8815446. [Epub ahead of print]
    Recessive PPTC7 deficiency triggers excessive mitophagy to cause a severe inborn error of metabolism with hypomyelinating leukodystrophy.
    Keri-Lyn Kozul, Ali AlAsmari, Essa Alharby, Reem Zakzouk, Youmian Yan, Aziza Mushiba, Anwar Alhamad, Emily Harrelson, Maya Ayach, Kevin Cho, Heba Zahid, Francisca De Luna Vitorino, Richard Searfoss, Xingyu Liu, Mohammed A Saleh, Muhammad Latif, Lianjie Wei, Ali Aldawood, Laila Alsuhaibani, Mohammed Abdulhafith Bafail, Thiago Menezes, Manar Samman, Hannah Pletcher, Ibrahim Sandokji, Walaa Borhan, Tessa Lochetto, Abrar Alamri, Wedad Mudayfin, Mazin Syed, Leah Shriver, Benjamin Garcia, Eissa Faqeih, Gary Patti, Natalie Niemi, Naif Almontashiri.
      The mitochondrial phosphatase PPTC7 has emerged as a potent regulator of metabolism and mitophagy as its global knockout leads to perinatal lethality in mice. However, no known Mendelian diseases have been linked to PPTC7 deficiency, rendering its role in human pathophysiology unclear. Here, we identify two independent homozygous variants in PPTC7 : a missense variant, p.D158N, and a duplication variant (c.*57dup) within the 3` untranslated region (UTR). These variants were detected in three patients from two unrelated families presenting with a primary mitochondrial disease characterized by hypomyelinating leukodystrophy, recurrent metabolic and lactic acidosis, and anemia with immune dysregulation. Patient samples, including plasma and primary fibroblasts, showed robust metabolic and mitochondrial dysfunction, with substantial phenotypic overlap with Pptc7 knockout murine fibroblast models. PPTC7 patient fibroblasts carrying the p.D158N variant and CRISPR-knocked in cells to model the 3`UTR variant showed hallmarks of excessive BNIP3- and NIX-mediated mitophagy, including aberrant mitochondrial morphology, diminished mitochondrial protein expression, and increased mt-Keima flux. Critically, increased mitophagy in these cellular models was rescued by exogenous PPTC7 expression, confirming dysfunction derives from loss of this mitochondrial phosphatase. Mechanistically, we found that the p.D158N variant, affecting a highly conserved residue, disrupts metal binding to compromise both the enzymatic phosphatase function of PPTC7 as well as its negative regulation of BNIP3 and NIX. Collectively, these data provide the first known cases with a recessive inborn error of mitophagy due to PPTC7 deficiency and underscore the importance of this mitochondrial phosphatase in maintaining metabolic health and balanced mitophagy.
    DOI:  https://doi.org/10.21203/rs.3.rs-8815446/v1
  5. Autophagy Rep. 2026 ;5(1): 2629624
    Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
    Mariana Joaquim, Maike F Dohrn, Arnaud Chevrollier, Mafalda Escobar-Henriques.
      Mitochondria are central hubs for cellular fitness, empowered by plastic remodeling of their shape, proteome composition, and/or metabolic state. MFN2 (mitofusin 2) mediates mitochondrial fusion and ensures adaptations in response to metabolic changes and stresses. Besides this canonical role, MFN2 serves as a communication hub with other organelles. It tethers mitochondria to the endoplasmic reticulum (ER), lipid droplets, and peroxisomes, regulating calcium buffering, apoptosis, lipid biosynthesis, and lipolysis. Dysfunctional MFN2 causes the hereditary neuropathy Charcot-Marie-Tooth type 2A (CMT2A) and is linked to several metabolic diseases. In a recent publication, we described another fusion-independent role of MFN2 in proteostasis and mitophagy. MFN2 binds the chaperone HSPA8/HSC70 (heat shock protein family A [Hsp70] member 8) and the proteasome, a key function in maintaining mitochondrial and cellular protein quality control, which appears to be lost in the context of CMT2A-associated MFN2 variants.
    Keywords:  Charcot–Marie–Tooth type 2A (CMT2A); HSPA8/HSC70; MFN2; protein import; proteasome; VCP/p97; PINK1; apoptosis; mitophagy; proteostasis
    DOI:  https://doi.org/10.1080/27694127.2026.2629624
  6. Nat Commun. 2026 Feb 24.
    Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.
    Eleanor Meader, Morgan T Walcheck, Mindy R Leder, Patrice Delaney, Marcelo Falchetti, Ran Jing, Christopher Li, Netra K Kambli, Paul J Wrighton, Wade W Sugden, Mohamad A Najia, Isaac M Oderberg, Vivian M Taylor, Zachary C LeBlanc, Eleanor D Quenzer, Sung-Eun Lim, Thorsten Schlaeger, George Q Daley, Wolfram Goessling, Trista E North.
      Embryonic hematopoietic stem and progenitor cells (HSPCs) have the clinically valuable ability to undergo substantial proliferative expansion while maintaining multipotency, which remains difficult to replicate in culture. Here, we show that newly specified HSPCs achieve this unique state by precise spatio-temporal regulation of reactive oxygen species (ROS) via Bnip3lb-associated developmentally-programmed mitophagy, a distinct autophagic regulatory mechanism from that of adult HSPCs. While ROS drives HSPC specification in the dorsal aorta, scRNAseq and live-imaging of mitophagy-reporter zebrafish indicate that mitophagy initiates during endothelial-to-hematopoietic transition and colonization of secondary niches. Knockdown of bnip3lb reduces mitophagy and HSPC numbers in the caudal hematopoietic tissue by promoting myeloid-biased differentiation and apoptosis, which can be rescued by antioxidant exposure. Conversely, chemical or genetic induction of mitophagy enhances embryonic HSPC and lymphoid progenitor numbers. Significantly, compound-mediated mitophagy activation improves ex vivo function of HSPCs derived from human-induced pluripotent stem cells, enhancing serial-replating hematopoietic colony forming potential.
    DOI:  https://doi.org/10.1038/s41467-026-69593-9
  7. Autophagy Rep. 2026 ;5(1): 2626661
    Microautophagy: current understanding of its molecular mechanisms and functions.
    Yasuyoshi Sakai, Christian Behrends, Jayanta Debnath, Masanori Izumi, Andreas Jenny, Maurizio Molinari, Shuhei Nakamura, Masahide Oku, Marisa S Otegui, Laura Santambrogio, Han-Ming Shen, Tomohiko Taguchi, Michael Thumm, Takashi Ushimaru, Zhiping Xie, Ana Maria Cuervo, Fulvio Reggiori.
      Microautophagy (MI-autophagy) is an umbrella term for intracellular degradative pathways that entail the invagination or protrusion of the limiting membranes of endolysosomal compartments, that is, late endosomes and mammalian lysosomes or yeast and plant vacuoles, followed by pinching-off of the membrane into the lumen of the organelle. During these processes, the material specifically and nonspecifically targeted for degradation is sequestered within the invaginating or protuberating membrane. In contrast to macroautophagy, the molecular mechanisms underlying MI-autophagy are largely unknown due to their diversity and complexity in location, regulation and molecular machinery requirements. Here, we review recent progress in the field of MI-autophagy, describing the molecular basis and functions of the MI-autophagic pathways reported to date in eukaryotic cells, from yeast to mammalian and plant cells.
    Keywords:  Endosomes; lysosomes; multivesicular bodies; organelle turnover; proteolysis; vacuole
    DOI:  https://doi.org/10.1080/27694127.2026.2626661
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