bims-tofagi Biomed News
on Mitophagy
Issue of 2026–04–05
nine papers selected by
Michele Frison, University of Cambridge
  1. Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
  2. Why selection for mitochondrial quality drives the evolution of sexes.
  3. STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
  4. Decidual protein induced by progesterone enhances HIF-1α stability to promote mitophagy and glycolysis.
  5. PINK1 and STUB1 pathway orchestrates peroxisomal selective autophagy by PEX13 depletion.
  6. The role of TOMM20 in Mediating TERT translocation to mitochondria and its impact on mitophagy in membranous nephropathy.
  7. Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression.
  8. The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer.
  9. Targeting REV-ERBα/BNIP3 axis attenuates pulmonary arterial hypertension by repressing mitophagy in mice.
  1. Autophagy. 2026 Mar 31. 1-3
    Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
    Polyxeni Papadea, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal germline, the genetic bottleneck and purifying selection, are counteracting this decline but the exact molecular mechanisms and their possible link remain incompletely understood. To address this, we investigated the role of autophagy and mtDNA copy number in shaping purifying selection during maternal mtDNA transmission. Using a carefully designed breeding strategy in mice expressing a proofreading-deficient mitochondrial DNA polymerase, we generated animals carrying random mtDNA mutations and simultaneously introduced moderately decreased or increased mtDNA copy number, or impaired autophagy. Mutation patterns in control animals closely resembled those observed in humans, showing strong purifying selection against non-synonymous mutations, particularly in oxidative phosphorylation (OXPHOS) genes. Our recent work provides new insight by identifying autophagy as a key mediator of germline purifying selection of mtDNA. Moreover, we demonstrate that mtDNA copy number directly influences the efficiency of purifying selection, revealing that these two processes are functionally interconnected.
    Keywords:  Bottleneck; maternal transmission; mitochondria; mitophagy; mtDNA mutations
    DOI:  https://doi.org/10.1080/15548627.2026.2650772
  2. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250076. [Epub ahead of print]381(1947):
    Why selection for mitochondrial quality drives the evolution of sexes.
    Nick Lane, Andrew Pomiankowski.
      The evolution of sexes is closely tied to uniparental inheritance (UPI) of mitochondrial DNA (mtDNA), where only females transmit mtDNA. Unlike nuclear DNA, mtDNA is highly polyploid and never evolved to be part of meiotic sex. Modelling shows that UPI increases mtDNA mutational variance, enhancing selection for high-quality mtDNA and promoting the emergence of sexes from mating types in unicellular eukaryotes. Paternal control of mitochondrial transfer favours some degree of mtDNA leakage, whereas maternal control favours strict UPI, leading to sexual conflict driving turnover in transmission mechanisms. In multicellular organisms, mitotic segregation of mtDNA increases variance in gametes, again facilitating selection. Surprisingly, germline evolution seems to reflect mtDNA mutation rates: plants and sessile metazoans have low rates and produce gametes from somatic cells, while bilaterians and ctenophores with higher rates sequester germlines with restricted cell division. High mtDNA ploidy in oocytes allows early embryonic cell division without replication, reducing mutational variance across tissues and enhancing somatic fitness. Germline mtDNA quality is maintained by mitotic over-proliferation of germ cells and the selective transfer of mtDNA into primordial oocytes linked with massive apoptotic germ-cell atresia. Overall, selection for mtDNA quality elucidates the evolution of sexes and the architecture of the female germline. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  Balbiani body; germline; mitochondria; mitochondrial mutation; mtDNA; oogenesis; sexes; uniparental inheritance
    DOI:  https://doi.org/10.1098/rstb.2025.0076
  3. Cell Rep. 2026 Mar 27. pii: S2211-1247(26)00261-5. [Epub ahead of print]45(4): 117183
    STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
    Jin-Yi Lin, Ze-Bo Huang, Shi-Qi Zhang, Yong Wu, Ling-Jun Cheng, Xiangzheng Gao, Sofie Lautrup, Shu-Qin Cao, Junping Pan, Dade Rong, Ruixue Ai, Hayden Weng Siong Tan, Liming Wang, Haihe Wang, Han-Ming Shen, Evandro F Fang, Guang Lu.
      PINK1 is a master regulator of PINK1-parkin-mediated mitophagy, a key process for maintaining mitochondrial homeostasis. The precise regulation of PINK1 is therefore essential for orchestrating mitophagy. While proteolytic processing of PINK1 and degradation of cleaved PINK1 via the N-end rule under basal conditions have been extensively characterized, the mechanisms governing full-length PINK1 degradation upon mitochondrial damage remain enigmatic. Here, we demonstrate that PINK1 undergoes ubiquitination and proteasomal degradation during mitophagy through the coordinated action of STUB1 and VCP/p97. Depletion of STUB1 stabilizes full-length PINK1, which paradoxically impairs mitophagy through the acceleration of parkin degradation. At the organismal level, the STUB1-VCP axis plays an important role in neuronal mitophagy-related memory and learning capacities in the roundworm C. elegans. Congruently, this axis is impaired in the postmortem brain tissues from patients with Alzheimer's disease compared with cognitively normal controls. Collectively, our findings support STUB1-VCP as a molecular calibrator that fine-tunes full-length PINK1 levels to enable efficient mitophagy and maintain mitochondrial homeostasis.
    Keywords:  Alzheimer’s disease; CP: metabolism; CP: molecular biology; PINK1; STUB1; VCP/p97; autophagy; mitophagy; parkin; ubiquitination-proteasome system
    DOI:  https://doi.org/10.1016/j.celrep.2026.117183
  4. FEBS J. 2026 Apr 01.
    Decidual protein induced by progesterone enhances HIF-1α stability to promote mitophagy and glycolysis.
    Baopeng Tian, Jie Shen, Xuanning Chu, Yannan Zhou, Hao Li, Lei Wang, Min Guo, Jie Dou.
      Mitophagy, the process of removing mitochondria through the autophagy-lysosome pathway, is crucial for maintaining cellular homeostasis. However, its regulatory mechanisms and pathological implications remain poorly understood. In our study, we revealed that decidual protein induced by progesterone (DEPP) plays a significant role in mitophagy through the DEPP-HIF-1α-BNIP3/NIX axis. Our findings indicate that interaction between DEPP and hypoxia-inducible factor 1-alpha (HIF-1α) enhances HIF-1α stability, thereby promoting the transcription of HIF-1 target genes. The enhanced protein stability of HIF-1α not only activates mitophagy by stimulating the transcription of BCL2-interacting protein 3 (BNIP3) and BCL2-interacting protein 3-like (BNIP3L; also known as NIX) mRNA but also influences cellular metabolic reprogramming by promoting the transcription of glycolysis-related genes. In conclusion, our findings suggest that DEPP may act as a potential regulator of mitophagy and HIF-1α, playing an important role in maintaining cellular metabolic and energy homeostasis.
    Keywords:  BNIP3; DEPP; HIF‐1α; NIX; glycolysis; mitophagy
    DOI:  https://doi.org/10.1111/febs.70489
  5. Cell Death Differ. 2026 Apr 02.
    PINK1 and STUB1 pathway orchestrates peroxisomal selective autophagy by PEX13 depletion.
    Doo Sin Jo, Na Yeon Park, Ae-Kyeong Kim, Sunhoe Bang, Yong Hwan Kim, Ji-Eun Bae, Kyunghee Noh, Jeong-Hoon Kim, Min Jae Lee, Seong-Kyu Choe, Peter K Kim, Jongkyeong Chung, Kyu-Sun Lee, Dong-Hyung Cho.
      Peroxisomes are dynamic organelles essential for lipid metabolism, oxidative balance, and cellular stress responses. Their dysfunction contributes to various diseases, including metabolic and neurodegenerative disorders. Selective autophagy, or pexophagy, preserves peroxisomal quality by removing damaged or excess peroxisomes. Here, we propose a novel ATM-PINK1-STUB1-ABCD3-SQSTM1 signaling cascade that orchestrates pexophagy in response to peroxisomal impairment. Through siRNA screening, we find that PINK1 is a key regulator of pexophagy induced by PEX13 depletion. PINK1 phosphorylates STUB1, enhancing its E3 ligase activity to ubiquitinate ABCD3, which in turn recruits SQSTM1 for peroxisomal degradation. We further identify that ATM activates PINK1 under peroxisomal stress, linking cellular stress signaling to organelle quality control. These findings provide new insights into the molecular mechanisms underlying peroxisome turnover and may have implications for therapeutic strategies targeting diseases related to peroxisomal dysfunction.
    DOI:  https://doi.org/10.1038/s41418-026-01726-5
  6. BMC Nephrol. 2026 Apr 01.
    The role of TOMM20 in Mediating TERT translocation to mitochondria and its impact on mitophagy in membranous nephropathy.
    Limiao Yang, Hongle Yang, Mingming Zhang, Feifei Zhang, Xiaomei Liu, Zhiping Zhang, Jing Wang, Xiaolu Chen, Yuexuan Wang, Rui Zhang, Weihao Li.
      
    Keywords:  Membranous nephropathy; Mitochondrial translocation; Mitophagy; Telomerase reverse transcriptase; The outer mitochondrial membrane 20
    DOI:  https://doi.org/10.1186/s12882-026-04910-4
  7. Cancer Lett. 2026 Mar 26. pii: S0304-3835(26)00220-X. [Epub ahead of print]647 218457
    Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression.
    Nicolás Georges-Calderón, Camila Fuentes, Yessia Hidalgo, Felipe Grunenwald, José Corrales-Bermúdez, Aliosha I Figueroa-Valdés, Mirliana Ramírez-Pereira, Gloria Arriagada, Fernando J Bustos, Constanza Ahumada-Marchant, Mercedes López, Francisca Alcayaga-Miranda.
      Recent evidence establishes that melanoma cells actively uptake mitochondria from stromal cells; however, the mitochondrial release in a physiological context remains unstudied. Here, we show that melanoma cells release dysfunctional mitochondria into the extracellular space through a predominantly non-vesicular route. Using melanocyte Melan-a and melanoma B16-F1 and B16-F10 cell lines, we observed increased extracellular mitochondrial release in malignant cells. Electron microscopy revealed these mitochondria lacked cristae and were primarily free organelles. Membrane potential analysis confirmed their dysfunctional state. Mitophagy analysis using mtKeima showed that, under oxidative stress, melanoma cells failed to activate canonical mitophagy and instead upregulated mitochondrial release as an alternative MQC mechanism. Western blot analysis revealed a fission-biased mitochondrial network in melanoma cells, with elevated phospho-DRP1/DRP1 ratio, and a tendency to reduce MFN1 and OPA1. Together with PINK1/ATG7 downregulation and BNIP3/NIX upregulation, suggest a secretory mitophagy phenotype. Tumor-derived mitochondria were detected in both the tumor microenvironment and plasma of melanoma-bearing mice, with extracellular mitochondria levels correlating with tumor burden. Plasma from melanoma patients exhibited elevated levels of TOMM20+ mitochondria compared to healthy donors. Transcriptomic analysis of The Cancer Genome Atlas melanoma cohort revealed that high expression of MQC-related genes DRP1 and BNIP3L was associated with worse prognosis. Collectively, our findings uncover a tumor-intrinsic, non-canonical MQC pathway that releases dysfunctional mitochondria. This mechanism establishes a new paradigm of tumor-host systemic communication, wherein circulating tumor-derived mitochondria might actively influence disease progression. These findings open avenues for developing non-invasive biomarkers and therapeutic strategies targeting mitochondrial release.
    Keywords:  Biomarkers; Extracellular mitochondria; Melanoma; Mitochondrial quality control; Secretory mitophagy
    DOI:  https://doi.org/10.1016/j.canlet.2026.218457
  8. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00163-2. [Epub ahead of print]86(7): 1260-1274.e4
    The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer.
    Maimon E Hubbi, Catherine L Wang, Yasir Suhail, Nadia L Almasri, Jane Xie, Erin E Hollander, Kshitiz, Alexander Muir, Ben Z Stanger, Chi V Dang.
      Ferroptosis is an iron-dependent form of cell death converging on lipid peroxidation first identified by examining compounds with enhanced lethality to KRAS mutant cells. Despite over 90% of pancreatic ductal adenocarcinoma (PDAC) tumors harboring KRAS mutations, PDAC exhibits relative resistance to ferroptosis compared with other tumor types, and the mechanisms behind this resistance remain unclear. Here, we report that exposure to pancreatic tumor interstitial fluid in synergy with hypoxia induced robust protection against ferroptosis in a manner dependent on the hypoxia-inducible transcription factor 2 (HIF-2). HIF-2 upregulates the expression of both components of the system Xc- cystine transporter and transsulfuration pathway enzymes CBS and CTH to increase intracellular cysteine levels, enabling anti-ferroptotic glutathione production. HIF-2 also induces the Parkin mitophagy factor and suppresses mitochondrial function and reactive oxygen species (ROS) generation. Altogether, our findings uncover an unforeseen role of the HIF-2 transcription factor as a coordinator of anti-ferroptotic mechanisms in pancreatic cancer.
    Keywords:  HIF-2 transcription factor; ferroptosis; hypoxia; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.007
  9. Nat Commun. 2026 Apr 02.
    Targeting REV-ERBα/BNIP3 axis attenuates pulmonary arterial hypertension by repressing mitophagy in mice.
    Lejia Qiu, Tingting Lu, Jiayang Zhang, Min Liu, Hui Wang, Wenyu Li, Changxiao Ma, Shuyao Li, Baoyin Ren, Qiong Wang, Fenling Fan, Hu Xu, Feng Zheng, Youfei Guan, Xiaoyan Zhang, Guangrui Yang, Lihong Chen.
      Pulmonary arterial hypertension (PAH) is a life-threatening metabolic disorder. Nuclear receptors REV-ERBα and REV-ERBβ are established regulators of circadian rhythm and metabolic homeostasis, however their roles in PAH remain unclear. Using Rev-erbα+/-, VSMC-specific Rev-erbα-/-, and Rev-erbβ-/- mice (only male mice were used in the study), along with pharmacological activation and AAV-mediated overexpression, we found that Rev-erbα deficiency, particularly in vascular smooth muscle cells (VSMCs), exacerbates Su5416+hypoxia (SuHx)-induced PAH, whereas REV-ERBα activation or overexpression alleviates disease. In contrast, Rev-erbβ loss does not affect PAH. Notably, late-stage administration of REV-ERBα agonist significantly improves established PAH. Mechanistically, REV-ERBα directly represses Bnip3 transcription, thereby inhibiting BNIP3-driven mitophagy and improving mitochondrial function in hypoxic pulmonary artery smooth muscle cells (PASMCs). Bnip3 knockdown phenocopies REV-ERBα activation, while Bnip3 overexpression abrogates REV-ERBα's anti-proliferative effects and accelerates PAH. Collectively, REV-ERBα protects against PAH by inhibiting BNIP3-driven mitophagy and preserving mitochondrial homeostasis in PASMCs. Targeting the REV-ERBα/BNIP3 axis holds promise as a circadian-based therapeutic strategy for PAH.
    DOI:  https://doi.org/10.1038/s41467-026-71189-2
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