bims-mecmid 2021-09-19 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2021–09–19
nine papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Cristae-dependent quality control of the mitochondrial genome.
Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase.
Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics.
Mapping Activity-Dependent Quasi-stationary States of Mitochondrial Membranes with Graphene-Induced Energy Transfer Imaging.
PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism: Drp1-dependent mechanism.
Decreased dynamin-related protein 1-related mitophagy induces myocardial apoptosis in the aging heart.
CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1.
Delayed Diagnosis of Autosomal Dominant Optic Atrophy Diagnosis until the Seventh Decade of Life.
Reduced mitochondrial fission and impaired energy metabolism in human primary skeletal muscle cells of Megaconial Congenital Muscular Dystrophy.

Sci Adv. 2021 Sep 03. 7(36): eabi8886

Cristae-dependent quality control of the mitochondrial genome.

Christopher Jakubke, Rodaria Roussou, Andreas Maiser, Christina Schug, Felix Thoma, David Bunk, David Hörl, Heinrich Leonhardt, Peter Walter, Till Klecker, Christof Osman.

[Figure: see text].

DOI: https://doi.org/10.1126/sciadv.abi8886
Redox Biol. 2021 Sep 10. pii: S2213-2317(21)00284-6. [Epub ahead of print]46 102125

Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase.

Jonathan V Dietz, Mathilda M Willoughby, Robert B Piel, Teresa A Ross, Iryna Bohovych, Hannah G Addis, Jennifer L Fox, William N Lanzilotta, Harry A Dailey, James A Wohlschlegel, Amit R Reddi, Amy E Medlock, Oleh Khalimonchuk.

  Heme is an essential cofactor required for a plethora of cellular processes in eukaryotes. In metazoans the heme biosynthetic pathway is typically partitioned between the cytosol and mitochondria, with the first and final steps taking place in the mitochondrion. The pathway has been extensively studied and its biosynthetic enzymes structurally characterized to varying extents. Nevertheless, understanding of the regulation of heme synthesis and factors that influence this process in metazoans remains incomplete. Therefore, we investigated the molecular organization as well as the physical and genetic interactions of the terminal pathway enzyme, ferrochelatase (Hem15), in the yeast Saccharomyces cerevisiae. Biochemical and genetic analyses revealed dynamic association of Hem15 with Mic60, a core component of the mitochondrial contact site and cristae organizing system (MICOS). Loss of MICOS negatively impacts Hem15 activity, affects the size of the Hem15 high-mass complex, and results in accumulation of reactive and potentially toxic tetrapyrrole precursors that may cause oxidative damage. Restoring intermembrane connectivity in MICOS-deficient cells mitigates these cytotoxic effects. These data provide new insights into how heme biosynthetic machinery is organized and regulated, linking mitochondrial architecture-organizing factors to heme homeostasis.

Keywords:  Ferrochelatase; Heme; MICOS; Mitochondria; Yeast

DOI:  https://doi.org/10.1016/j.redox.2021.102125
J Biol Chem. 2021 Sep 13. pii: S0021-9258(21)00998-4. [Epub ahead of print] 101196

Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics.

William T King, Christopher L Axelrod, Elizabeth R M Zunica, Robert C Noland, Gangarao Davuluri, Hisashi Fujioka, Bernard Tandler, Kathryn Pergola, Gerlinda E Hermann, Richard C Rogers, Sandra López-Domènech, Wagner S Dantas, Krisztian Stadler, Charles L Hoppel, John P Kirwan.

  Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, inhibition of ATP-stimulated calcium flux, and impaired substrate oxidation stimulated by calcium levels. The insights obtained herein suggest that DRP1 regulates fatty acid oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.

Keywords:  calcium signaling; dynamin-related protein 1; mitochondrial dynamics; skeletal muscle; β-oxidation

DOI:  https://doi.org/10.1016/j.jbc.2021.101196
Nano Lett. 2021 Sep 14.

Mapping Activity-Dependent Quasi-stationary States of Mitochondrial Membranes with Graphene-Induced Energy Transfer Imaging.

Sufi O Raja, Alexey I Chizhik, Christoph F Schmidt, Jörg Enderlein, Arindam Ghosh.

  Graphene-induced energy transfer (GIET) was recently introduced for sub-nanometric axial localization of fluorescent molecules. GIET relies on near-field energy transfer from an optically excited fluorophore to a single sheet of graphene. Recently, we demonstrated its potential by determining the distance between two leaflets of supported lipid bilayers. Here, we use GIET imaging for mapping quasi-stationary states of the inner and outer mitochondrial membranes before and during adenosine triphosphate (ATP) synthesis. We trigger the ATP synthesis state in vitro by activating mitochondria with precursor molecules. Our results demonstrate that the inner membrane approaches the outer membrane, while the outer membrane does not show any measurable change in average axial position upon activation. The inter-membrane space is reduced by ∼2 nm. This direct experimental observation of the subtle dynamics of mitochondrial membranes and the change in intermembrane distance upon activation is relevant for our understanding of mitochondrial function.

Keywords:  GIET; IM-OM distance; hyperosmotic shock; quasi-stationary states

DOI:  https://doi.org/10.1021/acs.nanolett.1c02672
Mol Oncol. 2021 Sep 17.

PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism: Drp1-dependent mechanism.

Luca Simula, Ylenia Antonucci, Giorgia Scarpelli, Valeria Cancila, Alessandra Colamatteo, Simona Manni, Biagio De Angelis, Concetta Quintarelli, Claudio Procaccini, Giuseppe Matarese, Claudio Tripodo, Silvia Campello.

  Programmed cell death-1 (PD-1) signaling downregulates the T cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1pos CD8+ T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared to PD-1neg counterparts. Also, PD-1pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondria fragmentation following T cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor-infiltrating PD-1pos CD8+ T cells seems to be a mechanism exploited by PD-1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anti-cancer immune response in future immunotherapy approaches.

Keywords:  Drp1; PD-1; T cell; mitochondria; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1002/1878-0261.13103
Acta Biochim Biophys Sin (Shanghai). 2021 Sep 17. pii: gmab112. [Epub ahead of print]

Decreased dynamin-related protein 1-related mitophagy induces myocardial apoptosis in the aging heart.

Xin Wei, Y E Wu, Wen Wang, Suli Zhang, Dan Liu, Huirong Liu.

  An increase in cardiomyocyte apoptosis is the main contributor to the observed high morbidity of cardiac disease during aging. Mitochondria play important roles in cardiac apoptosis, and dynamin-related protein 1 (Drp1) is the critical factor that participates in mitochondrial fission and induces mitophagy to maintain mitochondria quality. However, whether Drp1 is involved in the increase of apoptosis in aging heart remains unclear. The purpose of this study was to determine whether Drp1 participates in inducing the apoptosis through regulating mitophagy in aging myocardium. To explore the effect of mitophagy and apoptosis in aging heart, we detected the expression of COX IV and the co-localization of COX IV and LC3 II, which reflect mitophagy, and measured adenosine triphosphate and reactive oxygen species contents, which reflect mitochondrial injury. Cell apoptosis was detected by measuring the activity of caspase-3 and the expression of cleaved caspase-3 and further confirmed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The results showed an increase in apoptosis and a decrease in mitophagy in aging cardiomyocytes, and apoptosis was ameliorated after the induction of mitophagy by carbonyl cyanide m-chlorophenyl hydrazone (a mitophagy activator) in D-galactose (D-gal)-induced senescence H9c2 cells. To clarify the role of Drp1 in apoptosis, we knocked down Drp1 by transfecting si-Drp1, or overexpressed Drp1 in senescent cells, and then detected mitophagy, mitochondrial injury, and apoptosis. The data showed that downregulated Drp1 induces mitochondrial damage and apoptosis. In addition, to explore the regulatory relationship between Drp1 and phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy, we detected the expressions of PINK1 and Parkin after the overexpression of Drp1 in the D-gal group cells and found that Drp1-mediated mitophagy inhibited the PINK1/Parkin pathway in senescent cells. Our results demonstrated that insufficient Drp1 induces cardiomyocyte apoptosis by inhibiting mitophagy, and Drp1 affects the PINK1/Parkin pathway of mitophagy in the aging heart.

Keywords:  Drp1; PINK1; aging; apoptosis; mitophagy

DOI:  https://doi.org/10.1093/abbs/gmab112
Biochem Biophys Res Commun. 2021 Aug 13. pii: S0006-291X(21)01179-7. [Epub ahead of print]577 80-88

CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1.

Jinghai Hua, Zhiming Gao, Shaochun Zhong, Bocui Wei, Jianbing Zhu, Ru Ying.

  Atherosclerosis still remains the leading cause of morbidity and mortality worldwide, and deeper understanding of target signaling that protect from the atherosclerosis progression may provide novel therapeutic strategies. CDGSH iron-sulfur domain-containing protein 1 (CISD1) is a protein localized on the outer membrane of mitochondria, and plays key roles in regulating cell death and oxidative stress. However, its potential on atherosclerosis development and the underlying mechanisms are largely unknown. Here, in our study, we found markedly decreased CISD1 expression in lipid-laden THP1 macrophages. Notably, lentivirus (LV)-mediated CISD1 over-expression remarkably ameliorated lipid deposition in macrophages stimulated by ox-LDL. Furthermore, cellular total ROS and mitochondrial ROS generation, and impairment of mitochondrial membrane potential (MMP) were highly induced by ox-LDL in THP1 cells, while being considerably reversed upon CISD1 over-expression. Inflammatory response caused by ox-LDL was also significantly restrained in macrophages with CISD1 over-expression. Mechanistically, we found that CISD1 could interact with dynamin-related protein 1 (Drp1). Intriguingly, CISD1-improved mitochondrial dysfunction and inflammation in ox-LDL-treated macrophages were strongly abolished by Drp1 over-expression, indicating that Drp1 suppression might be necessary for CISD1 to perform its protective effects in vitro. In high fat diet (HFD)-fed apolipoprotein E-deficient (ApoE-/-) mice, tail vein injection of lentiviral vector expressing CISD1 remarkably decreased atherosclerotic lesion area, serum LDL cholesterol levels and triglyceride contents. Inflammatory response, cellular total and mitochondrial ROS production, and Drp1 expression levels in aorta tissues were also dramatically ameliorated in HFD-fed ApoE-/- mice, contributing to the inhibition of atherosclerosis in vivo. Therefore, improving CISD1 expression may be a novel therapeutic strategy for atherosclerosis treatment.

Keywords:  Atherosclerosis; CISD1; Drp1; Inflammation; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.bbrc.2021.08.023
Can J Ophthalmol. 2021 Sep 14. pii: S0008-4182(21)00300-8. [Epub ahead of print]

Delayed Diagnosis of Autosomal Dominant Optic Atrophy Diagnosis until the Seventh Decade of Life.

Subahari Raviskanthan, Pranati Ahuja, Peter W Mortensen, Dan Milea, Andrew G Lee.

DOI: https://doi.org/10.1016/j.jcjo.2021.08.007
Sci Rep. 2021 Sep 13. 11(1): 18161

Reduced mitochondrial fission and impaired energy metabolism in human primary skeletal muscle cells of Megaconial Congenital Muscular Dystrophy.

Evrim Aksu-Menges, Cemil Can Eylem, Emirhan Nemutlu, Merve Gizer, Petek Korkusuz, Haluk Topaloglu, Beril Talim, Burcu Balci-Hayta.

Megaconial Congenital Muscular Dystrophy (CMD) is a rare autosomal recessive disorder characterized by enlarged mitochondria located mainly at the periphery of muscle fibers and caused by mutations in the Choline Kinase Beta (CHKB) gene. Although the pathogenesis of this disease is not well understood, there is accumulating evidence for the presence of mitochondrial dysfunction. In this study, we aimed to investigate whether imbalanced mitochondrial dynamics affects mitochondrial function and bioenergetic efficiency in skeletal muscle cells of Megaconial CMD. Immunofluorescence, confocal and transmission electron microscopy studies revealed impaired mitochondrial network, morphology, and localization in primary skeletal muscle cells of Megaconial CMD. The organelle disruption was specific only to skeletal muscle cells grown in culture. The expression levels of mitochondrial fission proteins (DRP1, MFF, FIS1) were found to be decreased significantly in both primary skeletal muscle cells and tissue sections of Megaconial CMD by Western blotting and/or immunofluorescence analysis. The metabolomic and fluxomic analysis, which were performed in Megaconial CMD for the first time, revealed decreased levels of phosphonucleotides, Krebs cycle intermediates, ATP, and altered energy metabolism pathways. Our results indicate that reduced mitochondrial fission and altered mitochondrial energy metabolism contribute to mitochondrial dysmorphology and dysfunction in the pathogenesis of Megaconial CMD.

DOI: https://doi.org/10.1038/s41598-021-97294-4