bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2025–02–23
seven papers selected by
Gavin McStay, Liverpool John Moores University
  1. Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
  2. Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
  3. PFOS causes lysosomes-regulated mitochondrial fission through TRPML1-VDAC1 and oligomerization of MCU/ATP5J2.
  4. SIRT3-Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease.
  5. Hypoxia induces ferroptotic cell death mediated by activation of the inner mitochondrial membrane fission protein MTP18/Drp1 in invertebrates.
  6. Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
  7. Mitochondrial alterations and signatures in hepatocellular carcinoma.
  1. Nature. 2025 Feb 19.
    Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
    Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.
      Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.
    DOI:  https://doi.org/10.1038/s41586-025-08590-2
  2. Nature. 2025 Feb 19.
    Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
    Kate McArthur, Michael T Ryan.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00303-z
  3. J Hazard Mater. 2025 Feb 20. pii: S0304-3894(25)00599-0. [Epub ahead of print]489 137685
    PFOS causes lysosomes-regulated mitochondrial fission through TRPML1-VDAC1 and oligomerization of MCU/ATP5J2.
    Wei Yang, Yu Li, Ruzhen Feng, Peiyao Liang, Kefan Tian, Lingli Hu, Kejing Wang, Tianming Qiu, Jingyuan Zhang, Xiance Sun, Xiaofeng Yao.
      Perfluorooctane sulfonate (PFOS), a listed persistent organic pollutant, poses risks to human health and is closely linked to chronic metabolic diseases. Although the role of mitochondrial fission in these diseases has garnered attention, whether and how PFOS induces mitochondrial fission remains obscure. Here, we found that PFOS induced mitochondrial fission, as demonstrated by the fragmentation of mitochondria and the upregulation of dynamin-related protein 1 (DRP1), phospho-DRP1 and mitochondrial fission protein 1 (FIS1) in human hepatocytes MIHA and mice liver. Blocking the calcium transfer from lysosomes to mitochondria that was executed by transient receptor potential mucolipin 1 (TRPML1) of lysosomes and voltage-dependent anion channel 1 (VDAC1) of mitochondria, did not affect PFOS-induced mitochondrial fission. In contrast, knockdown of TRPML1 or VDAC1 reversed this process. Knockdown of mitochondrial calcium uniporter (MCU), rather than inhibiting its activity, effectively alleviated PFOS-induced mitochondrial fission. Additionally, PFOS increased MCU oligomers without affecting MCU monomer. Inhibiting autophagy reversed the MCU oligomerization. Further investigation unveiled the interactions of MCU with VDAC1, TRPML1, mitochondrial Fo complex subunit F2 (ATP5J2) and DRP1 in PFOS-exposed mice liver and MIHA cells. We also discovered that knockdown of ATP5J2 alleviated PFOS-induced mitochondrial fission. Ulteriorly, PFOS upregulated ATP5J2 that underwent oligomerization. Knockdown of MCU reversed the increase in ATP5J2. Our study uncovers the presence and molecular basics of lysosomes-regulated mitochondrial fission under PFOS exposure, explains the regulatory pathways on MCU and ATP5J2 oligomerization and their pivotal roles in mitochondrial fission, highlighting the involvement of mitochondrial fission in PFOS-related health risks.
    Keywords:  ATP synthase; Perfluorooctane sulfonate; Toxicity mechanism
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.137685
  4. Adv Sci (Weinh). 2025 Feb 20. e2411235
    SIRT3-Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease.
    Ye Xi, Kai Tao, Xiaomin Wen, Dayun Feng, Zifan Mai, Hui Ding, Honghui Mao, Mingming Wang, Qian Yang, Jie Xiang, Jie Zhang, Shengxi Wu.
      Dysregulation of mitochondrial dynamics is a key contributor to the pathogenesis of Parkinson's disease (PD). Aberrant mitochondrial fission induced by dynamin-related protein 1 (DRP1) causes mitochondrial dysfunction in dopaminergic (DA) neurons. However, the mechanism of DRP1 activation and its role in PD progression remain unclear. In this study, Mass spectrometry analysis is performed and identified a significant increased DRP1 acetylation at lysine residue 711 (K711) in the mitochondria under oxidative stress. Enhanced DRP1K711 acetylation facilitated DRP1 oligomerization, thereby exacerbating mitochondrial fragmentation and compromising the mitochondrial function. DRP1K711 acetylation also affects mitochondrial DRP1 recruitment and fission independent of canonical S616 phosphorylation. Further analysis reveals the critical role of sirtuin (SIRT)-3 in deacetylating DRP1K711, thereby regulating mitochondrial dynamics and function. SIRT3 agonists significantly inhibit DRP1K711 acetylation, rescue DA neuronal loss, and improve motor function in a PD mouse model. Conversely, selective knockout of SIRT3 in DA neurons exacerbates DRP1K711 acetylation, leading to increased DA neuronal damage, neuronal death, and worsened motor dysfunction. Notably, this study identifies a novel mechanism involving aberrant SIRT3-mediated DRP1 acetylation at K711 as a key driver of mitochondrial dysfunction and DA neuronal death in PD, revealing a potential target for PD treatment.
    Keywords:  DRP1K711; Parkinson's disease; SIRT3; acetylation; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1002/advs.202411235
  5. J Biol Chem. 2025 Feb 17. pii: S0021-9258(25)00175-9. [Epub ahead of print] 108326
    Hypoxia induces ferroptotic cell death mediated by activation of the inner mitochondrial membrane fission protein MTP18/Drp1 in invertebrates.
    Jiaqi Liu, Xichao Sun, Yijie Wu, Zhimin Lv, Na Zhou, Chao Bian, Shengming Sun.
      Hypoxia and ischemia damage sensitive organelles such as mitochondria, thus mitochondrial dysfunction contributes to metabolic disorders in crustaceans under hypoxia. The mechanisms associated with ferroptosis in hypoxic disorders have not been determined in crustaceans. In particular, the early molecular events of mitochondrial dynamics in crustaceans require clarification. In this study, two evolutionarily conserved mitochondrial fission proteins, Drp1 and MTP18, were identified in the oriental river prawn (Macrobrachium nipponense). In vitro, ferroptosis-mediated impairment of mitochondrial membrane potential was induced by hypoxia in oriental river prawn hemocytes. In hypoxia-induced hemocytes, activation of Drp1 by increased phosphorylation at S616 was identified. Drp1 mitochondrial translocation also increased, and mitochondrial fusion-related protein expression decreased in vivo. Altered mitochondrial fission-fusion dynamics have been linked to mitochondrial dysfunction, inducing a classic ferroptosis mechanism. Marf overexpression or Drp1 knockdown protected against mitochondrial dysfunction and ferroptotic cell death in vitro. Furthermore, hypoxia-induced mitochondrial fission was verified to be driven by the Drp1/MTP18 interaction. Under hypoxia, MTP18 transcription was increased by the binding of activated HIF-1α to hypoxia response elements (HREs) in its promoter. Conjointly, MTP18 knockdown resulted in less apoptosis and decreased prawn mortality in gill tissue in vitro; suggesting that adaptation to hypoxia involves a vital function of MTP18. In conclusion, we uncovered a conserved role of mitochondrial fission in hypoxia-induced ferroptotic cell death. Therefore, we suggest that specific modulation of MTP18/DRP1-mediated mitochondrial dynamics might be a potential therapeutic strategy in hypoxic stress-induced tissue injury of invertebrates.
    Keywords:  Drp1; ferroptosis; hypoxia; invertebrate; mitochondrial fission
    DOI:  https://doi.org/10.1016/j.jbc.2025.108326
  6. bioRxiv. 2025 Jan 31. pii: 2024.12.21.629919. [Epub ahead of print]
    Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
    Jorge L Cueva-Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo.
      Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.
    DOI:  https://doi.org/10.1101/2024.12.21.629919
  7. Cancer Metastasis Rev. 2025 Feb 18. 44(1): 34
    Mitochondrial alterations and signatures in hepatocellular carcinoma.
    Tsung-Hsien Chen, Shu-Hsien Lin, Ming-Yang Lee, Hsiang-Chen Wang, Kun-Feng Tsai, Chu-Kuang Chou.
      Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer worldwide. Its primary risk factors are chronic liver diseases such as metabolic fatty liver disease, non-alcoholic steatohepatitis, and hepatitis B and C viral infections. These conditions contribute to a specific microenvironment in liver tumors which affects mitochondrial function. Mitochondria are energy producers in cells and are responsible for maintaining normal functions by controlling mitochondrial redox homeostasis, metabolism, bioenergetics, and cell death pathways. HCC involves abnormal mitochondrial functions, such as accumulation of reactive oxygen species, oxidative stress, hypoxia, impairment of the mitochondrial unfolded protein response, irregularities in mitochondrial dynamic fusion/fission mechanisms, and mitophagy. Cell death mechanisms, such as necroptosis, pyroptosis, ferroptosis, and cuproptosis, contribute to hepatocarcinogenesis and play a significant role in chemoresistance. The relationship between mitochondrial dynamics and HCC is thus noteworthy. In this review, we summarize the recent advances in mitochondrial alterations and signatures in HCC and attempt to elucidate its molecular biology. Here, we provide an overview of the mitochondrial processes involved in hepatocarcinogenesis and offer new insights into the molecular pathology of the disease. This may help guide future research focused on improving patient outcomes using innovative therapies.
    Keywords:  Chemoresistance; Hepatocarcinogenesis; Hepatocellular carcinoma; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s10555-025-10251-9
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