bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024‒05‒26
28 papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mitochondria at the crossroads of health and disease.
  2. TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
  3. Systemic phospho-defective and phospho-mimetic Drp1 mice exhibit normal growth and development with altered anxiety-like behavior.
  4. Serine 39 in the GTP-binding domain of Drp1 is involved in shaping mitochondrial morphology.
  5. SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
  6. Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet-mitochondria tethering to enhance β-oxidation and tumor cell proliferation.
  7. CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.
  8. Mitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk.
  9. Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.
  10. Mitochondria-ER-PM contacts regulate mitochondrial division and PI(4)P distribution.
  11. KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions.
  12. NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons.
  13. A mitochondrial carrier transports glycolytic intermediates to link cytosolic and mitochondrial glycolysis in the human gut parasite Blastocystis.
  14. Mitochondrial clearance and increased HSF-1 activity are coupled to promote longevity in fasted Caenorhabditis elegans.
  15. Visualization of cristae and mtDNA interactions via STED nanoscopy using a low saturation power probe.
  16. Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
  17. KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy.
  18. Decoding the Enigma: Translation Termination in Human Mitochondria.
  19. The molecular machinery for maturation of primary mtDNA transcripts.
  20. RNA degradation in human mitochondria: the journey is not finished.
  21. Origins of tissue and cell-type specificity in mitochondrial DNA (mtDNA) disease.
  22. Tools for editing the mammalian mitochondrial genome.
  23. Molecular and cellular consequences of mitochondrial DNA double-stranded breaks.
  24. Central dogma rates in human mitochondria.
  25. Illuminating mitochondrial translation through mouse models.
  26. Mitochondrial molecular genetics and human disease.
  27. Coordinating mitochondrial translation with assembly of the OXPHOS complexes.
  28. Mitochondrial DNA release and sensing in innate immune responses.
  1. Cell. 2024 May 23. pii: S0092-8674(24)00463-X. [Epub ahead of print]187(11): 2601-2627
    Mitochondria at the crossroads of health and disease.
    Anu Suomalainen, Jodi Nunnari.
      Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.
    DOI:  https://doi.org/10.1016/j.cell.2024.04.037
  2. Nat Cell Biol. 2024 May 23.
    TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
    Hao Liu, Cien Zhen, Jianming Xie, Zhenhuan Luo, Lin Zeng, Guojun Zhao, Shaohua Lu, Haixia Zhuang, Hualin Fan, Xia Li, Zhaojie Liu, Shiyin Lin, Huilin Jiang, Yuqian Chen, Jiahao Cheng, Zhiyu Cao, Keyu Dai, Jinhua Shi, Zhaohua Wang, Yongquan Hu, Tian Meng, Chuchu Zhou, Zhiyuan Han, Huansen Huang, Qinghua Zhou, Pengcheng He, Du Feng.
      When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.
    DOI:  https://doi.org/10.1038/s41556-024-01419-6
  3. iScience. 2024 Jun 21. 27(6): 109874
    Systemic phospho-defective and phospho-mimetic Drp1 mice exhibit normal growth and development with altered anxiety-like behavior.
    Arisa Ikeda, Miho Iijima, Hiromi Sesaki.
      Mitochondrial division controls the size, distribution, and turnover of this essential organelle. A dynamin-related GTPase, Drp1, drives membrane division as a force-generating mechano-chemical enzyme. Drp1 is regulated by multiple mechanisms, including phosphorylation at two primary sites: serine 579 and serine 600. While previous studies in cell culture systems have shown that Drp1 S579 phosphorylation promotes mitochondrial division, its physiological functions remained unclear. Here, we generated phospho-mimetic Drp1 S579D and phospho-defective Drp1 S579R mice using the CRISPR-Cas system. Both mouse models exhibited normal growth, development, and breeding. We found that Drp1 is highly phosphorylated at S579 in brain neurons. Notably, the Drp1 S579D mice showed decreased anxiety-like behaviors, whereas the Drp1 S579R mice displayed increased anxiety-like behaviors. These findings suggest a critical role for Drp1 S579 phosphorylation in brain function. The Drp1 S579D and S579R mice thus offer valuable in vivo models for specific analysis of Drp1 S579 phosphorylation.
    Keywords:  Behavioral neuroscience; Biochemistry; Developmental neuroscience; Molecular biology; Molecular neuroscience; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.109874
  4. FEBS Open Bio. 2024 May 17.
    Serine 39 in the GTP-binding domain of Drp1 is involved in shaping mitochondrial morphology.
    Marvi Ghani, Bernadett Szabó, Mahmoud Alkhatibe, Hailemariam Amsalu, Peleg Zohar, Eszter Anna Janka, János András Mótyán, Krisztina Tar.
      Continuous fusion and fission are critical for mitochondrial health. In this study, we further characterize the role played by dynamin-related protein 1 (Drp1) in mitochondrial fission. We show that a single amino acid change in Drp1 at position 39 from serine to alanine (S39A) within the GTP-binding (GTPase) domain results in a fused mitochondrial network in human SH-SY5Y neuroblastoma cells. Interestingly, the phosphorylation of Ser-616 and Ser-637 of Drp1 remains unaffected by the S39A mutation, and mitochondrial bioenergetic profile and cell viability in the S39A mutant were comparable to those observed in the control. This leads us to propose that the serine 39 residue of Drp1 plays a crucial role in mitochondrial distribution through its involvement in the GTPase activity. Furthermore, this amino acid mutation leads to structural anomalies in the mitochondrial network. Taken together, our results contribute to a better understanding of the function of the Drp1 protein.
    Keywords:  Drp1; S39A; mitochondrial network collapse; single amino acid mutagenesis
    DOI:  https://doi.org/10.1002/2211-5463.13820
  5. Cell Stem Cell. 2024 May 14. pii: S1934-5909(24)00176-0. [Epub ahead of print]
    SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
    Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Takayuki Morikawa, Shinya Fujita, Kotaro Shide, Miho Haraguchi, Shinpei Tamaki, Takumi Mikawa, Hiroshi Kondoh, Hiroyasu Nakano, Kenta Sumiyama, Go Nagamatsu, Nobuhito Goda, Shinichiro Okamoto, Ayako Nakamura-Ishizu, Kazuya Shimoda, Makoto Suematsu, Toshio Suda, Keiyo Takubo.
      Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.
    Keywords:  SDHAF1; adenosine triphosphate; hematopoietic stem cell; mitochondria; stem cell aging; stem cell metabolism; thrombopoietin
    DOI:  https://doi.org/10.1016/j.stem.2024.04.023
  6. Nat Metab. 2024 May 21.
    Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet-mitochondria tethering to enhance β-oxidation and tumor cell proliferation.
    Ying Meng, Dong Guo, Liming Lin, Hong Zhao, Weiting Xu, Shudi Luo, Xiaoming Jiang, Shan Li, Xuxiao He, Rongxuan Zhu, Rongkai Shi, Liwei Xiao, Qingang Wu, Haiyan He, Jingjing Tao, Hongfei Jiang, Zheng Wang, Pengbo Yao, Daqian Xu, Zhimin Lu.
      Lipid droplet tethering with mitochondria for fatty acid oxidation is critical for tumor cells to counteract energy stress. However, the underlying mechanism remains unclear. Here, we demonstrate that glucose deprivation induces phosphorylation of the glycolytic enzyme phosphofructokinase, liver type (PFKL), reducing its activity and favoring its interaction with perilipin 2 (PLIN2). On lipid droplets, PFKL acts as a protein kinase and phosphorylates PLIN2 to promote the binding of PLIN2 to carnitine palmitoyltransferase 1A (CPT1A). This results in the tethering of lipid droplets and mitochondria and the recruitment of adipose triglyceride lipase to the lipid droplet-mitochondria tethering regions to engage lipid mobilization. Interfering with this cascade inhibits tumor cell proliferation, promotes apoptosis and blunts liver tumor growth in male mice. These results reveal that energy stress confers a moonlight function to PFKL as a protein kinase to tether lipid droplets with mitochondria and highlight the crucial role of PFKL in the integrated regulation of glycolysis, lipid metabolism and mitochondrial oxidation.
    DOI:  https://doi.org/10.1038/s42255-024-01047-2
  7. Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2405123121
    CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.
    Rachel Nechushtai, Linda Rowland, Ola Karmi, Henri-Baptiste Marjault, Thi Thao Nguyen, Shubham Mittal, Raheel S Ahmed, DeAna Grant, Camila Manrique-Acevedo, Faruck Morcos, José N Onuchic, Ron Mittler.
      Mitochondria play a central role in muscle metabolism and function. A unique family of iron-sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3-NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.
    Keywords:  Duchenne muscular dystrophy; NDUFV2; NEET/CISD proteins; complex I; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2405123121
  8. Nat Commun. 2024 May 20. 15(1): 4272
    Mitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk.
    Vivek Singh, Yuzuru Itoh, Samuel Del'Olio, Asem Hassan, Andreas Naschberger, Rasmus Kock Flygaard, Yuko Nobe, Keiichi Izumikawa, Shintaro Aibara, Juni Andréll, Paul C Whitford, Antoni Barrientos, Masato Taoka, Alexey Amunts.
      The mitoribosome translates mitochondrial mRNAs and regulates energy conversion that is a signature of aerobic life forms. We present a 2.2 Å resolution structure of human mitoribosome together with validated mitoribosomal RNA (rRNA) modifications, including aminoacylated CP-tRNAVal. The structure shows how mitoribosomal proteins stabilise binding of mRNA and tRNA helping to align it in the decoding center, whereas the GDP-bound mS29 stabilizes intersubunit communication. Comparison between different states, with respect to tRNA position, allowed us to characterize a non-canonical L1 stalk, and molecular dynamics simulations revealed how it facilitates tRNA transitions in a way that does not require interactions with rRNA. We also report functionally important polyamines that are depleted when cells are subjected to an antibiotic treatment. The structural, biochemical, and computational data illuminate the principal functional components of the translation mechanism in mitochondria and provide a description of the structure and function of the human mitoribosome.
    DOI:  https://doi.org/10.1038/s41467-024-48163-x
  9. Nat Commun. 2024 May 18. 15(1): 4244
    Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.
    Nathan P Ward, Sang Jun Yoon, Tyce Flynn, Amanda M Sherwood, Maddison A Olley, Juliana Madej, Gina M DeNicola.
      Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.
    DOI:  https://doi.org/10.1038/s41467-024-48695-2
  10. J Cell Biol. 2024 Sep 02. pii: e202308144. [Epub ahead of print]223(9):
    Mitochondria-ER-PM contacts regulate mitochondrial division and PI(4)P distribution.
    Jason C Casler, Clare S Harper, Antoineen J White, Heidi L Anderson, Laura L Lackner.
      The mitochondria-ER-cortex anchor (MECA) forms a tripartite membrane contact site between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM). The core component of MECA, Num1, interacts with the PM and mitochondria via two distinct lipid-binding domains; however, the molecular mechanism by which Num1 interacts with the ER is unclear. Here, we demonstrate that Num1 contains a FFAT motif in its C-terminus that interacts with the integral ER membrane protein Scs2. While dispensable for Num1's functions in mitochondrial tethering and dynein anchoring, the FFAT motif is required for Num1's role in promoting mitochondrial division. Unexpectedly, we also reveal a novel function of MECA in regulating the distribution of phosphatidylinositol-4-phosphate (PI(4)P). Breaking Num1 association with any of the three membranes it tethers results in an accumulation of PI(4)P on the PM, likely via disrupting Sac1-mediated PI(4)P turnover. This work establishes MECA as an important regulatory hub that spatially organizes mitochondria, ER, and PM to coordinate crucial cellular functions.
    DOI:  https://doi.org/10.1083/jcb.202308144
  11. J Cell Sci. 2024 May 24. pii: jcs.261728. [Epub ahead of print]
    KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions.
    Peace Atakpa-Adaji, Adelina Ivanova, Karolina Kujawa, Colin W Taylor.
      Inositol 1,4,5-trisphosphate receptors (IP3Rs) are high-conductance channels that allow the regulated redistribution of Ca2+ from the ER to the cytosol and, at specialised membrane contact sites (MCS), to other organelles. Only a subset of IP3Rs release Ca2+ to the cytosol in response to IP3. These 'licensed' IP3Rs are associated with Kras-induced actin-interacting protein (KRAP) beneath the plasma membrane. It is unclear whether KRAP regulates IP3Rs at MCS. We show, using simultaneous measurements of Ca2+ concentration in the cytosol and mitochondrial matrix, that KRAP also licenses IP3Rs to release Ca2+ to mitochondria. Loss of KRAP abolishes cytosolic and mitochondrial Ca2+ signals evoked by stimulation of IP3Rs via endogenous receptors. KRAP is located at ER-mitochondria membrane contact sites (ERMCS) populated by IP3R clusters. Using a proximity ligation assay between IP3R and voltage-dependent anion channel 1 (VDAC1), we show that loss of KRAP reduces the number of ERMCS. We conclude that KRAP regulates Ca2+ transfer from IP3Rs to mitochondria by both licensing IP3R activity and stabilizing ERMCS.
    Keywords:  Ca2+; Endoplasmic reticulum; HeLa cell; Histamine; IP3 receptor; KRAP; MCU; Membrane contact site; Mitochondria; Proximity ligation assay; VDAC1
    DOI:  https://doi.org/10.1242/jcs.261728
  12. J Cell Biol. 2024 Sep 02. pii: e202402006. [Epub ahead of print]223(9):
    NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons.
    Kaiden M Power, Ken C Nguyen, Andriele Silva, Shaneen Singh, David H Hall, Christopher Rongo, Maureen M Barr.
      Ciliopathies are often caused by defects in the ciliary microtubule core. Glutamylation is abundant in cilia, and its dysregulation may contribute to ciliopathies and neurodegeneration. Mutation of the deglutamylase CCP1 causes infantile-onset neurodegeneration. In C. elegans, ccpp-1 loss causes age-related ciliary degradation that is suppressed by a mutation in the conserved NEK10 homolog nekl-4. NEKL-4 is absent from cilia, yet it negatively regulates ciliary stability via an unknown, glutamylation-independent mechanism. We show that NEKL-4 was mitochondria-associated. Additionally, nekl-4 mutants had longer mitochondria, a higher baseline mitochondrial oxidation state, and suppressed ccpp-1∆ mutant lifespan extension in response to oxidative stress. A kinase-dead nekl-4(KD) mutant ectopically localized to ccpp-1∆ cilia and rescued degenerating microtubule doublet B-tubules. A nondegradable nekl-4(PEST∆) mutant resembled the ccpp-1∆ mutant with dye-filling defects and B-tubule breaks. The nekl-4(PEST∆) Dyf phenotype was suppressed by mutation in the depolymerizing kinesin-8 KLP-13/KIF19A. We conclude that NEKL-4 influences ciliary stability by activating ciliary kinesins and promoting mitochondrial homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202402006
  13. Elife. 2024 May 23. pii: RP94187. [Epub ahead of print]13
    A mitochondrial carrier transports glycolytic intermediates to link cytosolic and mitochondrial glycolysis in the human gut parasite Blastocystis.
    Eva Pyrihová, Martin S King, Alannah C King, M Rey Toleco, Mark van der Giezen, Edmund R S Kunji.
      Stramenopiles form a clade of diverse eukaryotic organisms, including multicellular algae, the fish and plant pathogenic oomycetes, such as the potato blight Phytophthora, and the human intestinal protozoan Blastocystis. In most eukaryotes, glycolysis is a strictly cytosolic metabolic pathway that converts glucose to pyruvate, resulting in the production of NADH and ATP (Adenosine triphosphate). In contrast, stramenopiles have a branched glycolysis in which the enzymes of the pay-off phase are located in both the cytosol and the mitochondrial matrix. Here, we identify a mitochondrial carrier in Blastocystis that can transport glycolytic intermediates, such as dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, across the mitochondrial inner membrane, linking the cytosolic and mitochondrial branches of glycolysis. Comparative analyses with the phylogenetically related human mitochondrial oxoglutarate carrier (SLC25A11) and dicarboxylate carrier (SLC25A10) show that the glycolytic intermediate carrier has lost its ability to transport the canonical substrates malate and oxoglutarate. Blastocystis lacks several key components of oxidative phosphorylation required for the generation of mitochondrial ATP, such as complexes III and IV, ATP synthase, and ADP/ATP carriers. The presence of the glycolytic pay-off phase in the mitochondrial matrix generates ATP, which powers energy-requiring processes, such as macromolecular synthesis, as well as NADH, used by mitochondrial complex I to generate a proton motive force to drive the import of proteins and molecules. Given its unique substrate specificity and central role in carbon and energy metabolism, the carrier for glycolytic intermediates identified here represents a specific drug and pesticide target against stramenopile pathogens, which are of great economic importance.
    Keywords:  Blastocystis; E. coli; S. cerevisiae; SLC25 mitochondrial carrier family; biochemistry; chemical biology; evolutionary biology; human; missing transport link; protists; thermostability shift assays; transport assays
    DOI:  https://doi.org/10.7554/eLife.94187
  14. iScience. 2024 Jun 21. 27(6): 109834
    Mitochondrial clearance and increased HSF-1 activity are coupled to promote longevity in fasted Caenorhabditis elegans.
    Nikolaos Tataridas-Pallas, Yahyah Aman, Rhianna Williams, Hannah Chapman, Kevin J H Cheng, Casandra Gomez-Paredes, Gillian P Bates, John Labbadia.
      Fasting has emerged as a potent means of preserving tissue function with age in multiple model organisms. However, our understanding of the relationship between food removal and long-term health is incomplete. Here, we demonstrate that in the nematode worm Caenorhabditis elegans, a single period of early-life fasting is sufficient to selectively enhance HSF-1 activity, maintain proteostasis capacity and promote longevity without compromising fecundity. These effects persist even when food is returned, and are dependent on the mitochondrial sirtuin, SIR-2.2 and the H3K27me3 demethylase, JMJD-3.1. We find that increased HSF-1 activity upon fasting is associated with elevated SIR-2.2 levels, decreased mitochondrial copy number and reduced H3K27me3 levels at the promoters of HSF-1 target genes. Furthermore, consistent with our findings in worms, HSF-1 activity is also enhanced in muscle tissue from fasted mice, suggesting that the potentiation of HSF-1 is a conserved response to food withdrawal.
    Keywords:  Biological sciences; Physiology; cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109834
  15. Light Sci Appl. 2024 May 24. 13(1): 116
    Visualization of cristae and mtDNA interactions via STED nanoscopy using a low saturation power probe.
    Wei Ren, Xichuan Ge, Meiqi Li, Jing Sun, Shiyi Li, Shu Gao, Chunyan Shan, Baoxiang Gao, Peng Xi.
      Mitochondria are crucial organelles closely associated with cellular metabolism and function. Mitochondrial DNA (mtDNA) encodes a variety of transcripts and proteins essential for cellular function. However, the interaction between the inner membrane (IM) and mtDNA remains elusive due to the limitations in spatiotemporal resolution offered by conventional microscopy and the absence of suitable in vivo probes specifically targeting the IM. Here, we have developed a novel fluorescence probe called HBmito Crimson, characterized by exceptional photostability, fluorogenicity within lipid membranes, and low saturation power. We successfully achieved over 500 frames of low-power stimulated emission depletion microscopy (STED) imaging to visualize the IM dynamics, with a spatial resolution of 40 nm. By utilizing dual-color imaging of the IM and mtDNA, it has been uncovered that mtDNA tends to habitat at mitochondrial tips or branch points, exhibiting an overall spatially uniform distribution. Notably, the dynamics of mitochondria are intricately associated with the positioning of mtDNA, and fusion consistently occurs in close proximity to mtDNA to minimize pressure during cristae remodeling. In healthy cells, >66% of the mitochondria are Class III (i.e., mitochondria >5 μm or with >12 cristae), while it dropped to <18% in ferroptosis. Mitochondrial dynamics, orchestrated by cristae remodeling, foster the even distribution of mtDNA. Conversely, in conditions of apoptosis and ferroptosis where the cristae structure is compromised, mtDNA distribution becomes irregular. These findings, achieved with unprecedented spatiotemporal resolution, reveal the intricate interplay between cristae and mtDNA and provide insights into the driving forces behind mtDNA distribution.
    DOI:  https://doi.org/10.1038/s41377-024-01463-9
  16. J Biol Chem. 2024 May 21. pii: S0021-9258(24)01904-5. [Epub ahead of print] 107403
    Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
    Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.
      Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional up-regulated of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally down-regulated in cellular and murine models of mitochondrial defects. We identified a role for the post-transcriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo, using a model of mitochondria-associated disease in C. elegans, that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107403
  17. Sci Rep. 2024 05 22. 14(1): 11721
    KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy.
    Capucine de Talhouët, Noemi Esteras, Marc P M Soutar, Benjamin O'Callaghan, Helene Plun-Favreau.
      It has recently been shown that KAT8, a genome-wide association study candidate risk gene for Parkinson's Disease, is involved in PINK1/Parkin-dependant mitophagy. The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal epigenetic remodelling complex. In the current study, we show that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibits the initial steps of the PINK1-dependant mitophagy process. More specifically, our study shows that following mitochondrial depolarisation induced by mitochondrial toxins, MG149 treatment inhibits PINK1-dependant mitophagy initiation by impairing PINK1 activation, and subsequent phosphorylation of Parkin and ubiquitin. While this inhibitory effect of MG149 on PINK1-activation is potent, MG149 treatment in the absence of mitochondrial toxins is sufficient to depolarise the mitochondrial membrane, recruit PINK1 and promote partial downstream recruitment of the autophagy receptor p62, leading to an increase in mitochondrial delivery to the lysosomes. Altogether, our study provides additional support for KAT8 as a regulator of mitophagy and autophagy processes.
    Keywords:  Autophagy; KAT8; MG149; Mitophagy; Parkinson’s disease
    DOI:  https://doi.org/10.1038/s41598-024-60602-9
  18. Hum Mol Genet. 2024 May 22. 33(R1): R42-R46
    Decoding the Enigma: Translation Termination in Human Mitochondria.
    Annika Krüger, Daria Kovalchuk, Dmitrii Shiriaev, Joanna Rorbach.
      Mitochondrial translation is a complex process responsible for the synthesis of essential proteins involved in oxidative phosphorylation, a fundamental pathway for cellular energy production. Central to this process is the termination phase, where dedicated factors play a pivotal role in ensuring accurate and timely protein production. This review provides a comprehensive overview of the current understanding of translation termination in human mitochondria, emphasizing structural features and molecular functions of two mitochondrial termination factors mtRF1 and mtRF1a.
    Keywords:  Mitochondrial translation; mitochondrial translation termination factors; mitoribosomes
    DOI:  https://doi.org/10.1093/hmg/ddae032
  19. Hum Mol Genet. 2024 May 22. 33(R1): R19-R25
    The molecular machinery for maturation of primary mtDNA transcripts.
    Ana Vučković, Christoph Freyer, Anna Wredenberg, Hauke S Hillen.
      Human mitochondria harbour a circular, polyploid genome (mtDNA) encoding 11 messenger RNAs (mRNAs), two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Mitochondrial transcription produces long, polycistronic transcripts that span almost the entire length of the genome, and hence contain all three types of RNAs. The primary transcripts then undergo a number of processing and maturation steps, which constitute key regulatory points of mitochondrial gene expression. The first step of mitochondrial RNA processing consists of the separation of primary transcripts into individual, functional RNA molecules and can occur by two distinct pathways. Both are carried out by dedicated molecular machineries that substantially differ from RNA processing enzymes found elsewhere. As a result, the underlying molecular mechanisms remain poorly understood. Over the last years, genetic, biochemical and structural studies have identified key players involved in both RNA processing pathways and provided the first insights into the underlying mechanisms. Here, we review our current understanding of RNA processing in mammalian mitochondria and provide an outlook on open questions in the field.
    Keywords:  Mitochondria; Mitochondriopathy; RNA; RNA Processing
    DOI:  https://doi.org/10.1093/hmg/ddae023
  20. Hum Mol Genet. 2024 May 22. 33(R1): R26-R33
    RNA degradation in human mitochondria: the journey is not finished.
    Giulia Santonoceto, Aneta Jurkiewicz, Roman J Szczesny.
      Mitochondria are vital organelles present in almost all eukaryotic cells. Although most of the mitochondrial proteins are nuclear-encoded, mitochondria contain their own genome, whose proper expression is necessary for mitochondrial function. Transcription of the human mitochondrial genome results in the synthesis of long polycistronic transcripts that are subsequently processed by endonucleases to release individual RNA molecules, including precursors of sense protein-encoding mRNA (mt-mRNA) and a vast amount of antisense noncoding RNAs. Because of mitochondrial DNA (mtDNA) organization, the regulation of individual gene expression at the transcriptional level is limited. Although transcription of most protein-coding mitochondrial genes occurs with the same frequency, steady-state levels of mature transcripts are different. Therefore, post-transcriptional processes are important for regulating mt-mRNA levels. The mitochondrial degradosome is a complex composed of the RNA helicase SUV3 (also known as SUPV3L1) and polynucleotide phosphorylase (PNPase, PNPT1). It is the best-characterized RNA-degrading machinery in human mitochondria, which is primarily responsible for the decay of mitochondrial antisense RNA. The mechanism of mitochondrial sense RNA decay is less understood. This review aims to provide a general picture of mitochondrial genome expression, with a particular focus on mitochondrial RNA (mtRNA) degradation.
    Keywords:  mitochondrial RNA decay; mitochondrial RNA surveillance; mitochondrial gene expression; polyadenylation
    DOI:  https://doi.org/10.1093/hmg/ddae043
  21. Hum Mol Genet. 2024 May 22. 33(R1): R3-R11
    Origins of tissue and cell-type specificity in mitochondrial DNA (mtDNA) disease.
    Stephen P Burr, Patrick F Chinnery.
      Mutations of mitochondrial (mt)DNA are a major cause of morbidity and mortality in humans, accounting for approximately two thirds of diagnosed mitochondrial disease. However, despite significant advances in technology since the discovery of the first disease-causing mtDNA mutations in 1988, the comprehensive diagnosis and treatment of mtDNA disease remains challenging. This is partly due to the highly variable clinical presentation linked to tissue-specific vulnerability that determines which organs are affected. Organ involvement can vary between different mtDNA mutations, and also between patients carrying the same disease-causing variant. The clinical features frequently overlap with other non-mitochondrial diseases, both rare and common, adding to the diagnostic challenge. Building on previous findings, recent technological advances have cast further light on the mechanisms which underpin the organ vulnerability in mtDNA diseases, but our understanding is far from complete. In this review we explore the origins, current knowledge, and future directions of research in this area.
    Keywords:  heteroplasmy; mitochondria; mtDNA; single cell
    DOI:  https://doi.org/10.1093/hmg/ddae059
  22. Hum Mol Genet. 2024 May 22. 33(R1): R92-R99
    Tools for editing the mammalian mitochondrial genome.
    Carlos T Moraes.
      The manipulation of animal mitochondrial genomes has long been a challenge due to the lack of an effective transformation method. With the discovery of specific gene editing enzymes, designed to target pathogenic mitochondrial DNA mutations (often heteroplasmic), the selective removal or modification of mutant variants has become a reality. Because mitochondria cannot efficiently import RNAs, CRISPR has not been the first choice for editing mitochondrial genes. However, the last few years witnessed an explosion in novel and optimized non-CRISPR approaches to promote double-strand breaks or base-edit of mtDNA in vivo. Engineered forms of specific nucleases and cytidine/adenine deaminases form the basis for these techniques. I will review the newest developments that constitute the current toolbox for animal mtDNA gene editing in vivo, bringing these approaches not only to the exploration of mitochondrial function, but also closer to clinical use.
    Keywords:  TALEN technology; base editing; gene modification; genetic enhancements; mitochondrial manipulation
    DOI:  https://doi.org/10.1093/hmg/ddae037
  23. Hum Mol Genet. 2024 May 22. 33(R1): R12-R18
    Molecular and cellular consequences of mitochondrial DNA double-stranded breaks.
    Chenxiao Yu, Samieh Asadian, Marco Tigano.
      Mitochondria are subcellular organelles essential for life. Beyond their role in producing energy, mitochondria govern various physiological mechanisms, encompassing energy generation, metabolic processes, apoptotic events, and immune responses. Mitochondria also contain genetic material that is susceptible to various forms of damage. Mitochondrial double-stranded breaks (DSB) are toxic lesions that the nucleus repairs promptly. Nevertheless, the significance of DSB repair in mammalian mitochondria is controversial. This review presents an updated view of the available research on the consequences of mitochondrial DNA DSB from the molecular to the cellular level. We discuss the crucial function of mitochondrial DNA damage in regulating processes such as senescence, integrated stress response, and innate immunity. Lastly, we discuss the potential role of mitochondrial DNA DSB in mediating the cellular consequences of ionizing radiations, the standard of care in treating solid tumors.
    Keywords:  innate immunity; integrated stress response; mitochondria; mitochondrial DNA; senescence
    DOI:  https://doi.org/10.1093/hmg/ddae048
  24. Hum Mol Genet. 2024 May 22. 33(R1): R34-R41
    Central dogma rates in human mitochondria.
    Erik McShane, L Stirling Churchman.
      In human cells, the nuclear and mitochondrial genomes engage in a complex interplay to produce dual-encoded oxidative phosphorylation (OXPHOS) complexes. The coordination of these dynamic gene expression processes is essential for producing matched amounts of OXPHOS protein subunits. This review focuses on our current understanding of the mitochondrial central dogma rates, highlighting the striking differences in gene expression rates between mitochondrial and nuclear genes. We synthesize a coherent model of mitochondrial gene expression kinetics, highlighting the emerging principles and emphasizing where more precise measurements would be beneficial. Such an understanding is pivotal for grasping the unique aspects of mitochondrial function and its role in cellular energetics, and it has profound implications for aging, metabolic disorders, and neurodegenerative diseases.
    Keywords:  gene regulation; mitochondrial DNA; mitonuclear balance; oxidative phosphorylation
    DOI:  https://doi.org/10.1093/hmg/ddae036
  25. Hum Mol Genet. 2024 May 22. 33(R1): R61-R79
    Illuminating mitochondrial translation through mouse models.
    Laetitia A Hughes, Oliver Rackham, Aleksandra Filipovska.
      Mitochondria are hubs of metabolic activity with a major role in ATP conversion by oxidative phosphorylation (OXPHOS). The mammalian mitochondrial genome encodes 11 mRNAs encoding 13 OXPHOS proteins along with 2 rRNAs and 22 tRNAs, that facilitate their translation on mitoribosomes. Maintaining the internal production of core OXPHOS subunits requires modulation of the mitochondrial capacity to match the cellular requirements and correct insertion of particularly hydrophobic proteins into the inner mitochondrial membrane. The mitochondrial translation system is essential for energy production and defects result in severe, phenotypically diverse diseases, including mitochondrial diseases that typically affect postmitotic tissues with high metabolic demands. Understanding the complex mechanisms that underlie the pathologies of diseases involving impaired mitochondrial translation is key to tailoring specific treatments and effectively targeting the affected organs. Disease mutations have provided a fundamental, yet limited, understanding of mitochondrial protein synthesis, since effective modification of the mitochondrial genome has proven challenging. However, advances in next generation sequencing, cryoelectron microscopy, and multi-omic technologies have revealed unexpected and unusual features of the mitochondrial protein synthesis machinery in the last decade. Genome editing tools have generated unique models that have accelerated our mechanistic understanding of mitochondrial translation and its physiological importance. Here we review the most recent mouse models of disease pathogenesis caused by defects in mitochondrial protein synthesis and discuss their value for preclinical research and therapeutic development.
    Keywords:  animal models; gene expression; mitochondria; protein synthesis
    DOI:  https://doi.org/10.1093/hmg/ddae020
  26. Hum Mol Genet. 2024 May 22. 33(R1): R1-R2
    Mitochondrial molecular genetics and human disease.
    Eric A Shoubridge, Antoni Barrientos.
      
    DOI:  https://doi.org/10.1093/hmg/ddae049
  27. Hum Mol Genet. 2024 May 22. 33(R1): R47-R52
    Coordinating mitochondrial translation with assembly of the OXPHOS complexes.
    Laura S Kremer, Peter Rehling.
      The mitochondrial oxidative phosphorylation (OXPHOS) system produces the majority of energy required by cells. Given the mitochondrion's endosymbiotic origin, the OXPHOS machinery is still under dual genetic control where most OXPHOS subunits are encoded by the nuclear DNA and imported into mitochondria, while a small subset is encoded on the mitochondrion's own genome, the mitochondrial DNA (mtDNA). The nuclear and mtDNA encoded subunits must be expressed and assembled in a highly orchestrated fashion to form a functional OXPHOS system and meanwhile prevent the generation of any harmful assembly intermediates. While several mechanisms have evolved in eukaryotes to achieve such a coordinated expression, this review will focus on how the translation of mtDNA encoded OXPHOS subunits is tailored to OXPHOS assembly.
    Keywords:  Coordination of translation and assembly; Gene expression; Mitochondria; OXPHOS assembly; Oxidative phosphorylation (OXPHOS); Translation
    DOI:  https://doi.org/10.1093/hmg/ddae025
  28. Hum Mol Genet. 2024 May 22. 33(R1): R80-R91
    Mitochondrial DNA release and sensing in innate immune responses.
    Jordyn J VanPortfliet, Cole Chute, Yuanjiu Lei, Timothy E Shutt, A Phillip West.
      Mitochondria are pleiotropic organelles central to an array of cellular pathways including metabolism, signal transduction, and programmed cell death. Mitochondria are also key drivers of mammalian immune responses, functioning as scaffolds for innate immune signaling, governing metabolic switches required for immune cell activation, and releasing agonists that promote inflammation. Mitochondrial DNA (mtDNA) is a potent immunostimulatory agonist, triggering pro-inflammatory and type I interferon responses in a host of mammalian cell types. Here we review recent advances in how mtDNA is detected by nucleic acid sensors of the innate immune system upon release into the cytoplasm and extracellular space. We also discuss how the interplay between mtDNA release and sensing impacts cellular innate immune endpoints relevant to health and disease.
    Keywords:  NLRP3; TLR9; cGAS-STING; inflammation; innate immunity; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.1093/hmg/ddae031
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