bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024‒01‒21
seven papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
  2. NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
  3. Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.
  4. Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
  5. Osteocyte mitochondria inhibit tumor development via STING-dependent antitumor immunity.
  6. Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
  7. Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury.
  1. EMBO J. 2024 Jan 15.
    In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
    Michelle Y Fry, Paula P Navarro, Pusparanee Hakim, Virly Y Ananda, Xingping Qin, Juan C Landoni, Sneha Rath, Zintis Inde, Camila Makhlouta Lugo, Bridget E Luce, Yifan Ge, Julie L McDonald, Ilzat Ali, Leillani L Ha, Benjamin P Kleinstiver, David C Chan, Kristopher A Sarosiek, Luke H Chao.
      Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria, while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and show a compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.
    Keywords:  Cristae Remodeling; Cryo-Electron Tomography; Cryo-Focused Ion Beam Milling; Mitochondrial Biology
    DOI:  https://doi.org/10.1038/s44318-024-00027-2
  2. Nat Commun. 2024 Jan 16. 15(1): 546
    NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
    Liang Yang, Zifeng Ruan, Xiaobing Lin, Hao Wang, Yanmin Xin, Haite Tang, Zhijuan Hu, Yunhao Zhou, Yi Wu, Junwei Wang, Dajiang Qin, Gang Lu, Kerry M Loomes, Wai-Yee Chan, Xingguo Liu.
      Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.
    DOI:  https://doi.org/10.1038/s41467-024-44808-z
  3. Nat Commun. 2024 Jan 19. 15(1): 611
    Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.
    Ason C Y Chiang, Jan Ježek, Peiqiang Mu, Ying Di, Anna Klucnika, Martin Jabůrek, Petr Ježek, Hansong Ma.
      Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII109) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemical assays and phenotypic analyses, we show that the CoIII109 polymorphism modulates cardiolipin binding to prevent complex IV instability caused by the CoIT300I mutation. This study demonstrates the feasibility of genetic interaction screens in animal mitochondrial DNA. It unwraps the complex intra-genomic interplays underlying disorders linked to mitochondrial DNA and how they influence disease expression.
    DOI:  https://doi.org/10.1038/s41467-024-44964-2
  4. Cell Rep. 2024 Jan 17. pii: S2211-1247(24)00009-3. [Epub ahead of print]43(2): 113681
    Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
    Madeleine J Twyning, Roberta Tufi, Thomas P Gleeson, Kinga M Kolodziej, Susanna Campesan, Ana Terriente-Felix, Lewis Collins, Federica De Lazzari, Flaviano Giorgini, Alexander J Whitworth.
      Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial Ca2+ can cause cell death. Disrupted mitochondrial function and Ca2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+ levels, as well as reduced mitochondrial Ca2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention.
    Keywords:  Alzheimer's disease; CP: Neuroscience; Drosophila; Huntington's disease; MCU; NCLX; Parkinson's disease; calcium overload; frontotemporal dementia; mitochondrial calcium; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2024.113681
  5. Sci Adv. 2024 Jan 19. 10(3): eadi4298
    Osteocyte mitochondria inhibit tumor development via STING-dependent antitumor immunity.
    Hao Zhou, Wenkan Zhang, Hengyuan Li, Fan Xu, Eloy Yinwang, Yucheng Xue, Tao Chen, Shengdong Wang, Zenan Wang, Hangxiang Sun, Fangqian Wang, Haochen Mou, Minjun Yao, Xupeng Chai, Jiahao Zhang, Mohamed Diaty Diarra, Binghao Li, Changqing Zhang, Junjie Gao, Zhaoming Ye.
      Bone is one of the most common sites of tumor metastases. During the last step of bone metastasis, cancer cells colonize and disrupt the bone matrix, which is maintained mainly by osteocytes, the most abundant cells in the bone microenvironment. However, the role of osteocytes in bone metastasis is still unclear. Here, we demonstrated that osteocytes transfer mitochondria to metastatic cancer cells and trigger the cGAS/STING-mediated antitumor response. Blocking the transfer of mitochondria by specifically knocking out mitochondrial Rho GTPase 1 (Rhot1) or mitochondrial mitofusin 2 (Mfn2) in osteocytes impaired tumor immunogenicity and consequently resulted in the progression of metastatic cancer toward the bone matrix. These findings reveal the protective role of osteocytes against cancer metastasis by transferring mitochondria to cancer cells and potentially offer a valuable therapeutic strategy for preventing bone metastasis.
    DOI:  https://doi.org/10.1126/sciadv.adi4298
  6. Cell Death Differ. 2024 Jan 18.
    Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
    Elena Marchesan, Alice Nardin, Sofia Mauri, Greta Bernardo, Vivek Chander, Simone Di Paola, Monica Chinellato, Sophia von Stockum, Joy Chakraborty, Stephanie Herkenne, Valentina Basso, Emilie Schrepfer, Oriano Marin, Laura Cendron, Diego L Medina, Luca Scorrano, Elena Ziviani.
      Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.
    DOI:  https://doi.org/10.1038/s41418-023-01251-9
  7. Cell Death Dis. 2024 Jan 15. 15(1): 51
    Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury.
    Ari Kwon, Na Young Lee, Jae-Hyun Yu, Myeung Gi Choi, Jeongwoo Park, Ja Hyun Koo.
      Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ) are the main effectors of the Hippo pathway and their dysregulation contributes to diseases in tissues including the liver. Although mitochondria are capable of transmitting signals to change transcriptomic landscape of diseased hepatocytes, such retrograde signaling and the related nuclear machinery are largely unknown. Here, we show that increased YAP activity is associated with mitochondrial stress during liver injury; and this is required for secondary inflammation, promoting hepatocyte death. Mitochondrial stress inducers robustly promoted YAP/TAZ dephosphorylation, nuclear accumulation, and target gene transcription. RNA sequencing revealed that the majority of mitochondrial stress transcripts required YAP/TAZ. Mechanistically, direct oxidation of RhoA by mitochondrial superoxide was responsible for PP2A-mediated YAP/TAZ dephosphorylation providing a novel physiological input for the Hippo pathway. Hepatocyte-specific Yap/Taz ablation suppressed acetaminophen-induced liver injury and blunted transcriptomic changes associated with the pathology. Our observations uncover unappreciated pathway of mitochondrial stress signaling and reveal YAP/TAZ activation as the mechanistic basis for liver injury progression.
    DOI:  https://doi.org/10.1038/s41419-024-06448-5
This page is being maintained by Thomas Krichel. It was last updated on 2024‒01‒22 at 21:05.