bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒10‒09
twelve papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes.
  2. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
  3. Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.
  4. Loss of Num1-mediated cortical dynein anchoring negatively impacts respiratory growth.
  5. Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer.
  6. Inter-organellar and systemic responses to impaired mitochondrial matrix protein import in skeletal muscle.
  7. RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.
  8. Independent regulation of mitochondrial DNA quantity and quality in Caenorhabditis elegans primordial germ cells.
  9. Defective Mitochondrial Quality Control during Dengue Infection Contributes to Disease Pathogenesis.
  10. Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue.
  11. Structural basis of Ca2+ uptake by mitochondrial calcium uniporter in mitochondria: a brief review.
  12. No role for nuclear transcription regulators in mammalian mitochondria?
  1. Nature. 2022 Oct 05.
    Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes.
    Wei Wei, Katherine R Schon, Greg Elgar, Andrea Orioli, Melanie Tanguy, Adam Giess, Marc Tischkowitz, Mark J Caulfield, Patrick F Chinnery.
      DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event-the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation1-3. Here we analyse whole-genome sequences from 66,083 people-including 12,509 people with cancer-and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape.
    DOI:  https://doi.org/10.1038/s41586-022-05288-7
  2. Cell Metab. 2022 Sep 28. pii: S1550-4131(22)00395-3. [Epub ahead of print]
    Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
    Erika Fernández-Vizarra, Sandra López-Calcerrada, Ana Sierra-Magro, Rafael Pérez-Pérez, Luke E Formosa, Daniella H Hock, María Illescas, Ana Peñas, Michele Brischigliaro, Shujing Ding, Ian M Fearnley, Charalampos Tzoulis, Robert D S Pitceathly, Joaquín Arenas, Miguel A Martín, David A Stroud, Massimo Zeviani, Michael T Ryan, Cristina Ugalde.
      The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show the co-existence of two separate MRC organizations in human cells and postmitotic tissues, C-MRC and S-MRC, defined by the preferential expression of three COX7A subunit isoforms, COX7A1/2 and SCAFI (COX7A2L). COX7A isoforms promote the functional reorganization of distinct co-existing MRC structures to prevent metabolic exhaustion and MRC deficiency. Notably, prevalence of each MRC organization is reversibly regulated by the activation state of the pyruvate dehydrogenase complex (PDC). Under oxidative conditions, the C-MRC is bioenergetically more efficient, whereas the S-MRC preferentially maintains oxidative phosphorylation (OXPHOS) upon metabolic rewiring toward glycolysis. We show a link between the metabolic signatures converging at the PDC and the structural and functional organization of the MRC, challenging the widespread notion of the MRC as a single functional unit and concluding that its structural heterogeneity warrants optimal adaptation to metabolic function.
    Keywords:  COX7A1–2; SCAFI/COX7RP/COX7A2L; bioenergetics; glycolysis; metabolic switch; mitochondria; oxidative metabolism; pyruvate dehydrogenase; respiratory chain organizations; respiratory supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.005
  3. Mol Cell. 2022 Oct 06. pii: S1097-2765(22)00895-4. [Epub ahead of print]82(19): 3661-3676.e8
    Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.
    Chen-Wei Tsai, Madison X Rodriguez, Anna M Van Keuren, Charles B Phillips, Hannah M Shushunov, Jessica E Lee, Anastacia M Garcia, Amrut V Ambardekar, Joseph C Cleveland, Julie A Reisz, Catherine Proenza, Kathryn C Chatfield, Ming-Feng Tsai.
      Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca2+ uptake properties to support their unique physiological functions.
    Keywords:  calcium channels; cardiac pathophysiology; cellular metabolism; intracellular calcium signaling; membrane-transport mechanisms; mitochondrial physiology; mitochondrial proteases; organellar channels; protein complexes
    DOI:  https://doi.org/10.1016/j.molcel.2022.09.006
  4. J Cell Sci. 2022 Oct 03. pii: jcs.259980. [Epub ahead of print]
    Loss of Num1-mediated cortical dynein anchoring negatively impacts respiratory growth.
    Antoineen J White, Clare S Harper, Erica M Rosario, Jonathan V Dietz, Hannah G Addis, Jennifer L Fox, Oleh Khalimonchuk, Laura L Lackner.
      Num1 is a multifunctional protein that both tethers mitochondria to the plasma membrane and anchors dynein to the cell cortex during nuclear inheritance. Previous work has examined the impact loss of Num1-based mitochondrial tethering has on dynein function in Saccharomyces cerevisiae; here, we elucidate its impact on mitochondrial function. We find that like mitochondria, Num1 is regulated by changes in metabolic state, with the protein levels and cortical distribution of Num1 differing between fermentative and respiratory growth conditions. In cells lacking Num1, we observe a reproducible respiratory growth defect, suggesting a role for Num1 in not only maintaining mitochondrial morphology, but also function. A structure-function approach revealed that, unexpectedly, Num1-mediated cortical dynein anchoring is important for normal growth under respiratory conditions. The severe respiratory growth defect in Δnum1 cells is not specifically due to dynein's canonical function in nuclear migration but is dependent on the presence of dynein, as deletion of DYN1 in Δnum1 cells partially rescues respiratory growth. We hypothesize that misregulated dynein present in cells that lack Num1 negatively impacts mitochondrial function resulting in defects in respiratory growth.
    Keywords:  membrane contact sites; mitochondria; organelle positioning
    DOI:  https://doi.org/10.1242/jcs.259980
  5. Oncogene. 2022 Oct 04.
    Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer.
    Woo Kyung Lee Doolittle, Sunmi Park, Seul Gi Lee, Seonhyang Jeong, Gibbeum Lee, Dongryeol Ryu, Kristina Schoonjans, Johan Auwerx, Jandee Lee, Young Suk Jo.
      Cancer progression is associated with metabolic reprogramming and causes significant intracellular stress; however, the mechanisms that link cellular stress and growth signalling are not fully understood. Here, we identified a mechanism that couples the mitochondrial stress response (MSR) with tumour progression. We demonstrated that the MSR is activated in a significant proportion of human thyroid cancers via the upregulation of heat shock protein D family members and the mitokine, growth differentiation factor 15. Our study also revealed that MSR triggered AKT/S6K signalling by activating mTORC2 via activating transcription factor 4/sestrin 2 activation whilst promoting leucine transporter and nutrient-induced mTORC1 activation. Importantly, we found that an increase in mtDNA played an essential role in MSR-induced mTOR activation and that crosstalk between MYC and MSR potentiated mTOR activation. Together, these findings suggest that the MSR could be a predictive marker for aggressive human thyroid cancer as well as a useful therapeutic target.
    DOI:  https://doi.org/10.1038/s41388-022-02484-7
  6. Commun Biol. 2022 Oct 05. 5(1): 1060
    Inter-organellar and systemic responses to impaired mitochondrial matrix protein import in skeletal muscle.
    Nirajan Neupane, Jayasimman Rajendran, Jouni Kvist, Sandra Harjuhaahto, Bowen Hu, Veijo Kinnunen, Yang Yang, Anni I Nieminen, Henna Tyynismaa.
      Effective protein import from cytosol is critical for mitochondrial functions and metabolic regulation. We describe here the mammalian muscle-specific and systemic consequences to disrupted mitochondrial matrix protein import by targeted deletion of the mitochondrial HSP70 co-chaperone GRPEL1. Muscle-specific loss of GRPEL1 caused rapid muscle atrophy, accompanied by shut down of oxidative phosphorylation and mitochondrial fatty acid oxidation, and excessive triggering of proteotoxic stress responses. Transcriptome analysis identified new responders to mitochondrial protein import toxicity, such as the neurological disease-linked intermembrane space protein CHCHD10. Besides communication with ER and nucleus, we identified crosstalk of distressed mitochondria with peroxisomes, in particular the induction of peroxisomal Acyl-CoA oxidase 2 (ACOX2), which we propose as an ATF4-regulated peroxisomal marker of integrated stress response. Metabolic profiling indicated fatty acid enrichment in muscle, a shift in TCA cycle intermediates in serum and muscle, and dysregulated bile acids. Our results demonstrate the fundamental importance of GRPEL1 and provide a robust model for detecting mammalian inter-organellar and systemic responses to impaired mitochondrial matrix protein import and folding.
    DOI:  https://doi.org/10.1038/s42003-022-04034-z
  7. Autophagy. 2022 Oct 06.
    RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.
    Michelle Tu, Shigeki Miyamoto.
      RHOA (ras homolog family member A) is a small G-protein that regulates a range of cellular processes including cell growth and survival. RHOA is a proximal downstream effector of G protein-coupled receptor coupling to GNA12/Gα12-GNA13/Gα13 proteins, and is activated in response to stretch and oxidative stress, functioning as a stress-response molecule. It has been demonstrated that RHOA signaling provides cardioprotection through inhibition of mitochondrial death pathways. Mitochondrial integrity is preserved not only by inhibition of mitochondrial death pathways but also by mitochondrial quality control mechanisms including mitophagy. One of the most well-established mechanisms of mitophagy is the mitochondrial membrane depolarization-dependent PINK1-PRKN/Parkin pathway. However, depolarization of the mitochondrial membrane potential is a late-stage event that occurs just before cell death, and additional intracellular mechanisms that enhance the PINK1-PRKN pathway have not been fully determined. We recently discovered that RHOA activation engages a unique mechanism to regulate PINK1 protein stability without inducing mitochondrial membrane depolarization, leading to increased mitophagy and protection against ischemia in cardiomyocytes. Our results suggest regulation of RHOA signaling as a potential strategy to enhance protective mitophagy against stress without compromising mitochondrial functions.
    Keywords:  Cardiomyocytes; PINK1, RHOA; ischemia; mitophagy, Parkin
    DOI:  https://doi.org/10.1080/15548627.2022.2132707
  8. Elife. 2022 Oct 06. pii: e80396. [Epub ahead of print]11
    Independent regulation of mitochondrial DNA quantity and quality in Caenorhabditis elegans primordial germ cells.
    Aaron Z A Schwartz, Nikita Tsyba, Yusuff Abdu, Maulik R Patel, Jeremy Nance.
      Mitochondria harbor an independent genome, called mitochondrial DNA (mtDNA), which contains essential metabolic genes. Although mtDNA mutations occur at high frequency, they are inherited infrequently, indicating that germline mechanisms limit their accumulation. To determine how germline mtDNA is regulated, we examined the control of mtDNA quantity and quality in C. elegans primordial germ cells (PGCs). We show that PGCs combine strategies to generate a low point in mtDNA number by segregating mitochondria into lobe-like protrusions that are cannibalized by adjacent cells, and by concurrently eliminating mitochondria through autophagy, reducing overall mtDNA content twofold. As PGCs exit quiescence and divide, mtDNAs replicate to maintain a set point of ~200 mtDNAs per germline stem cell. Whereas cannibalism and autophagy eliminate mtDNAs stochastically, we show that the kinase PTEN-induced kinase 1 (PINK1), operating independently of Parkin and autophagy, preferentially reduces the fraction of mutant mtDNAs. Thus, PGCs employ parallel mechanisms to control both the quantity and quality of the founding population of germline mtDNAs.
    Keywords:  C. elegans; PINK1; autophagy; bottleneck; cell biology; developmental biology; mitochondrial DNA; primordial germ cells; purifying selection
    DOI:  https://doi.org/10.7554/eLife.80396
  9. J Virol. 2022 Oct 05. e0082822
    Defective Mitochondrial Quality Control during Dengue Infection Contributes to Disease Pathogenesis.
    Bharati Singh, Kiran Avula, Shamim Akhtar Sufi, Nahid Parwin, Sayani Das, Mohd Faraz Alam, Subhashish Samantaray, Leelakrishna Bankapalli, Alankrita Rani, Kokavalla Poornima, Biswajita Prusty, Tareni P Mallick, Shubham K Shaw, Hiren Dodia, Shobhitendu Kabi, Trupti T Pagad, Sriprasad Mohanty, Gulam Hussain Syed.
      Mitochondrial fitness is governed by mitochondrial quality control pathways comprising mitochondrial dynamics and mitochondrial-selective autophagy (mitophagy). Disruption of these processes has been implicated in many human diseases, including viral infections. Here, we report a comprehensive analysis of the effect of dengue infection on host mitochondrial homeostasis and its significance in dengue disease pathogenesis. Despite severe mitochondrial stress and injury, we observed that the pathways of mitochondrial quality control and mitochondrial biogenesis are paradoxically downregulated in dengue-infected human liver cells. This leads to the disruption of mitochondrial homeostasis and the onset of cellular injury and necrotic death in the infected cells. Interestingly, dengue promotes global autophagy but selectively disrupts mitochondrial-selective autophagy (mitophagy). Dengue downregulates the expression of PINK1 and Parkin, the two major proteins involved in tagging the damaged mitochondria for elimination through mitophagy. Mitophagy flux assays also suggest that Parkin-independent pathways of mitophagy are also inactive during dengue infection. Dengue infection also disrupts mitochondrial biogenesis by downregulating the master regulators PPARγ and PGC1α. Dengue-infected cells release mitochondrial damage-associated molecular patterns (mtDAMPs) such as mitochondrial DNA into the cytosol and extracellular milieu. Furthermore, the challenge of naive immune cells with culture supernatants from dengue-infected liver cells was sufficient to trigger proinflammatory signaling. In correlation with our in vitro observations, dengue patients have high levels of cell-free mitochondrial DNA in their blood in proportion to the degree of thrombocytopenia. Overall, our study shows how defective mitochondrial homeostasis in dengue-infected liver cells can drive dengue disease pathogenesis. IMPORTANCE Many viruses target host cell mitochondria to create a microenvironment conducive to viral dissemination. Dengue virus also exploits host cell mitochondria to facilitate its viral life cycle. Dengue infection of liver cells leads to severe mitochondrial injury and inhibition of proteins that regulate mitochondrial quality control and biogenesis, thereby disrupting mitochondrial homeostasis. A defect in mitochondrial quality control leads to the accumulation of damaged mitochondria and promotes cellular injury. This leads to the release of mitochondrial damage-associated molecular patterns (mt-DAMPs) into the cell cytoplasm and extracellular milieu. These mt-DAMPs activate the naive immune cells and trigger proinflammatory signaling, leading to the release of cytokines and chemokines, which may trigger systemic inflammation and contribute to dengue disease pathogenesis. In correlation with this, we observed high levels of cell-free mitochondrial DNA in dengue patient blood. This study provides insight into how the disruption of mitochondrial quality control in dengue-infected cells can trigger inflammation and drive dengue disease pathogenesis.
    Keywords:  autophagy; dengue virus; inflammation; mitochondria; mitochondrial homeostasis; mitochondrial quality control; mitophagy; mt-DNA; necrosis
    DOI:  https://doi.org/10.1128/jvi.00828-22
  10. STAR Protoc. 2022 Sep 30. pii: S2666-1667(22)00618-9. [Epub ahead of print]3(4): 101738
    Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue.
    Lauren P Westhaver, Sarah Nersesian, Adam Nelson, Leah K MacLean, Emily B Carter, Jeanette E Boudreau.
      Mitochondrial damage-associated molecular patterns (mitoDAMPs) are released from cells dying uncontrolled, non-apoptotic deaths, usually secondary to disease or trauma. Here, we describe preparation of mitoDAMPs from mouse liver, but this protocol can be adapted for preparation of mitoDAMPs from other species and tissues. Tissues are dissociated and then processed to isolate mitochondria. Mitochondria are then sonicated and mitoDAMPs are collected by ultracentrifugation. This procedure produces μg quantities of mitoDAMPs and facilitates research to understand their impacts in health and disease. For complete details on the use and execution of this protocol, please refer to Westhaver et al. (2022).
    Keywords:  Cell Biology; Cell isolation; Cell separation/fractionation; Cell-based Assays; Immunology; Metabolomics
    DOI:  https://doi.org/10.1016/j.xpro.2022.101738
  11. BMB Rep. 2022 Oct 05. pii: 5705. [Epub ahead of print]
    Structural basis of Ca2+ uptake by mitochondrial calcium uniporter in mitochondria: a brief review.
    Jiho Yoo.
      Mitochondria are cellular organelles that perform various functions within cells. They are responsible for ATP production, cell-signal regulation, autophagy, and cell apoptosis. Because the mitochondrial proteins that perform these functions need Ca2+ ions for their activity, mitochondria have ion channels to selectively uptake Ca2+ ions from the cytoplasm. The ion channel known to play the most important role in the Ca2+ uptake in mitochondria is the mitochondrial calcium uniporter (MCU) holo-complex located in the inner mitochondrial membrane (IMM). This ion channel complex exists in the form of a complex consisting of the pore-forming protein through which the Ca2+ ions are transported into the mitochondrial matrix, and the auxiliary protein involved in regulating the activity of the Ca2+ uptake by the MCU holo-complex. Studies of this MCU holocomplex have long been conducted, but we didn't know in detail how mitochondria uptake Ca2+ ions through this ion channel complex or how the activity of this ion channel complex is regulated. Recently, the protein structure of the MCU holo-complex was identified, enabling the mechanism of Ca2+ uptake and its regulation by the MCU holo-complex to be confirmed. In this review, I will introduce the mechanism of action of the MCU holo-complex at the molecular level based on the Cryo-EM structure of the MCU holo-complex to help understand how mitochondria uptake the necessary Ca2+ ions through the MCU holo-complex and how these Ca2+ uptake mechanisms are regulated.
  12. Mol Cell. 2022 Sep 20. pii: S1097-2765(22)00899-1. [Epub ahead of print]
    No role for nuclear transcription regulators in mammalian mitochondria?
    Diana Rubalcava-Gracia, Rodolfo García-Villegas, Nils-Göran Larsson.
      Although the mammalian mtDNA transcription machinery is simple and resembles bacteriophage systems, there are many reports that nuclear transcription regulators, as exemplified by MEF2D, MOF, PGC-1α, and hormone receptors, are imported into mammalian mitochondria and directly interact with the mtDNA transcription machinery. However, the supporting experimental evidence for this concept is open to alternate interpretations, and a main issue is the difficulty in distinguishing indirect regulation of mtDNA transcription, caused by altered nuclear gene expression, from direct intramitochondrial effects. We provide a critical discussion and experimental guidelines to stringently assess roles of intramitochondrial factors implicated in direct regulation of mammalian mtDNA transcription.
    DOI:  https://doi.org/10.1016/j.molcel.2022.09.010
This page is being maintained by Thomas Krichel. It was last updated on 2022‒10‒12 at 21:23:57.