bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–12–10
eight papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.
  2. Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
  3. The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.
  4. The mystery of phospho-Drp1 with four adaptors in cell cycle: when mitochondrial fission couples to cell fate decisions.
  5. Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome.
  6. Apolipoproteins L1 and L3 control mitochondrial membrane dynamics.
  7. Collective mitochondrial dynamics resolve conflicting cellular tensions: From plants to general principles.
  8. A new role for phosphoinositides in regulating mitochondrial dynamics.
  1. Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01530-9. [Epub ahead of print]42(12): 113518
    De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.
    Jie Wan, Cheng Cheng, Jiajia Hu, Haiyan Huang, Qiaoqiao Han, Zuliang Jie, Qiang Zou, Jian-Hong Shi, Xiaoyan Yu.
      The dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ T cell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ T cell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ T cell metabolic fitness and antitumor function.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113518
  2. Sci Adv. 2023 Dec 08. 9(49): eadf9522
    Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
    Chao Chen, Hong Zheng, Edwin M Horwitz, Satomi Ando, Koichi Araki, Peng Zhao, Zhiguo Li, Mandy L Ford, Rafi Ahmed, Cheng-Kui Qu.
      Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.adf9522
  3. J Leukoc Biol. 2023 Dec 06. pii: qiad155. [Epub ahead of print]
    The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.
    Marissa G Stevens, Frank M Mason, Timothy N J Bullock.
      Pharmacological methods for promoting mitochondrial elongation suggest that effector T cells can be altered to support a memory T cell-like metabolic state. Such mitochondrial elongation approaches may enhance the development of immunological memory. Therefore, we hypothesized that deletion of the mitochondrial fission protein, DRP1, would lead to mitochondrial elongation and generate a large memory T cell population, an approach that could be exploited to enhance vaccination protocols. We find that, as expected, while deletion of DRP1 from T cells in dLckCre x Drp1flfl does compromise the magnitude and functionality of primary effector CD8+ T cells, a disproportionately large pool of memory CD8+ T cells does form. In contrast to primary effector CD8+ T cells, DRP1-deficient memory dLckCre x Drp1flfl CD8+ T cells mount a secondary response comparable to control memory T cells with respect to kinetics, magnitude, and effector capabilities. Interestingly, the relative propensity to form memory cells in the absence of DRP1 was neither associated with differentiation toward more memory precursor CD8+ T cells nor decreased cellular death of effector T cells. Instead, the tendency to form memory CD8+ T cells in the absence of DRP1 is associated with decreased TCR expression. Remarkably, in a competitive environment with DRP1-replete CD8+ T cells, the absence of DRP1 from CD8+ T cells compromised the generation of primary, memory and secondary responses, indicating that approaches targeting DRP1 need to be carefully tailored.
    Keywords:  CD8+ T cell; Cell Death; Cytokine; Differentiation; Memory T cell; Metabolism; Mitochondria; T cell receptor
    DOI:  https://doi.org/10.1093/jleuko/qiad155
  4. Cell Cycle. 2023 Dec 05. 1-19
    The mystery of phospho-Drp1 with four adaptors in cell cycle: when mitochondrial fission couples to cell fate decisions.
    Nian-Siou Wu, I-Chu Ma, Yi-Fan Lin, Huey-Jiun Ko, Joon-Khim Loh, Yi-Ren Hong.
      Recent study had deepened our knowledge of the mitochondrial dynamics to classify mitochondrial fission into two types. To further clarify the relationship between the two distinct fission machinery and the four major adaptors of Drp1, we propose a model of mechanism elucidating the multiple functions of phospho-Drp1 with its adaptors during cell cycle and providing in-depth insights into the molecular basis and evolutionary implications in depth. The model highlights not only the clustering characteristics of different phospho-Drp1 with respective subsets of mitochondrial pro-fission adaptors but also the correlation, crosstalk and shifting between different clustering of phosphorylated Drp1-adaptors during different key fission situations. Particularly, phospho-Drp1 (Ser616) couples with Mff/MiD51 to exert mitochondrial division and phospho-Drp1 (Ser637) couples with MiD49/Fis1 to execute mitophagy in M-phase. We then apply the model to address the relationship of mitochondrial dynamics to Parkinson's disease (PD) and carcinogenesis. Our proposed model is indeed compatible with current research results and pathological observations, providing promising directions for future treatment design.
    Keywords:  Drp1; Mitochondrial Adaptors; cell cycle; mitophagy; phosphorylation
    DOI:  https://doi.org/10.1080/15384101.2023.2289753
  5. Nat Commun. 2023 Dec 02. 14(1): 7991
    Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome.
    Thu Giang Nguyen, Christina Ritter, Eva Kummer.
      Mitochondria contain their own genetic information and a dedicated translation system to express it. The mitochondrial ribosome is assembled from mitochondrial-encoded RNA and nuclear-encoded ribosomal proteins. Assembly is coordinated in the mitochondrial matrix by biogenesis factors that transiently associate with the maturing particle. Here, we present a structural snapshot of a large mitoribosomal subunit assembly intermediate containing 7 biogenesis factors including the GTPases GTPBP7 and GTPBP10. Our structure illustrates how GTPBP10 aids the folding of the ribosomal RNA during the biogenesis process, how this process is related to bacterial ribosome biogenesis, and why mitochondria require two biogenesis factors in contrast to only one in bacteria.
    DOI:  https://doi.org/10.1038/s41467-023-43599-z
  6. Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01540-1. [Epub ahead of print]42(12): 113528
    Apolipoproteins L1 and L3 control mitochondrial membrane dynamics.
    Laurence Lecordier, Paul Heo, Jonas H Graversen, Dorle Hennig, Maria Kløjgaard Skytthe, Alexandre Cornet d'Elzius, Frédéric Pincet, David Pérez-Morga, Etienne Pays.
      Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A. Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO [knockout]) reduces PI4KB activity and triggers actomyosin reorganization. We report that APOL3, but not APOL1, controls PI4KB activity through interaction with PI4KB and neuronal calcium sensor-1 or calneuron-1. Both APOLs are present in Golgi-derived autophagy-related protein 9A vesicles, which are involved in PI4KB trafficking. Like APOL3-KO, APOL1Δ induces PI4KB dissociation from APOL3, linked to reduction of mitophagy flux and production of mitochondrial reactive oxygen species. APOL1 and APOL3, respectively, can interact with the mitophagy receptor prohibitin-2 and the mitophagosome membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). While APOL1 conditions PI4KB and APOL3 involvement in mitochondrion fission and mitophagy, APOL3-VAMP8 interaction promotes fusion between mitophagosomal and endolysosomal membranes. We propose that APOL3 controls mitochondrial membrane dynamics through interactions with the fission factor PI4KB and the fusion factor VAMP8.
    Keywords:  APOL1 risk variants; COVAN; COVID-19-associated nephropathy; CP: Cell biology; HIV-associated nephropathy; HIVAN; inflammation; interferon 1; kidney disease; mitochondrion fission/fusion; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113528
  7. Semin Cell Dev Biol. 2024 Mar 15. pii: S1084-9521(23)00169-6. [Epub ahead of print]156 253-265
    Collective mitochondrial dynamics resolve conflicting cellular tensions: From plants to general principles.
    Joanna M Chustecki, Iain G Johnston.
      Mitochondria play diverse and essential roles in eukaryotic cells, and plants are no exception. Plant mitochondria have several differences from their metazoan and fungal cousins: they often exist in a fragmented state, move rapidly on actin rather than microtubules, have many plant-specific metabolic features and roles, and usually contain only a subset of the complete mtDNA genome, which itself undergoes frequent recombination. This arrangement means that exchange and complementation is essential for plant mitochondria, and recent work has begun to reveal how their collective dynamics and resultant "social networks" of encounters support this exchange, connecting plant mitochondria in time rather than in space. This review will argue that this social network perspective can be extended to a "societal network", where mitochondrial dynamics are an essential part of the interacting cellular society of organelles and biomolecules. Evidence is emerging that mitochondrial dynamics allow optimal resolutions to competing cellular priorities; we will survey this evidence and review potential future research directions, highlighting that plant mitochondria can help reveal and test principles that apply across other kingdoms of life. In parallel with this fundamental cell biology, we also highlight the translational "One Health" importance of plant mitochondrial behaviour - which is exploited in the production of a vast amount of crops consumed worldwide - and the potential for multi-objective optimisation to understand and rationally re-engineer the evolved resolutions to these tensions.
    Keywords:  MtDNA inheritance; MtDNA maintenance; Multi-objective optimisation; Plant mitochondrial dynamics; Social network
    DOI:  https://doi.org/10.1016/j.semcdb.2023.09.005
  8. Adv Biol Regul. 2023 Nov 30. pii: S2212-4926(23)00047-7. [Epub ahead of print] 101001
    A new role for phosphoinositides in regulating mitochondrial dynamics.
    Sonia Raveena Lourdes, Rajendra Gurung, Saveen Giri, Christina A Mitchell, Meagan J McGrath.
      Phosphoinositides are a minor group of membrane-associated phospholipids that are transiently generated on the cytoplasmic leaflet of many organelle membranes and the plasma membrane. There are seven functionally distinct phosphoinositides, each derived via the reversible phosphorylation of phosphatidylinositol in various combinations on the inositol ring. Their generation and termination is tightly regulated by phosphatidylinositol-kinases and -phosphatases. These enzymes can function together in an integrated and coordinated manner, whereby the phosphoinositide product of one enzyme may subsequently serve as a substrate for another to generate a different phosphoinositide species. This regulatory mechanism not only enables the transient generation of phosphoinositides on membranes, but also more complex sequential or bidirectional conversion pathways, and phosphoinositides can also be transferred between organelles via membrane contacts. It is this capacity to fine-tune phosphoinositide signals that makes them ideal regulators of membrane organization and dynamics, through their recruitment of signalling, membrane altering and lipid transfer proteins. Research spanning several decades has provided extensive evidence that phosphoinositides are major gatekeepers of membrane organization, with roles in endocytosis, exocytosis, autophagy, lysosome dynamics, vesicular transport and secretion, cilia, inter-organelle membrane contact, endosome maturation and nuclear function. By contrast, there has been remarkably little known about the role of phosphoinositides at mitochondria - an enigmatic and major knowledge gap, with challenges in reliably detecting phosphoinositides at this site. Here we review recent significant breakthroughs in understanding the role of phosphoinositides in regulating mitochondrial dynamics and metabolic function.
    Keywords:  Mitochondria; Mitochondrial fission; PI(4,5)P(2); PI3P; PI4P; Phosphoinositide
    DOI:  https://doi.org/10.1016/j.jbior.2023.101001
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