bims-cytox1 Biomed news on
Cytochrome oxidase subunit 1
Issue of 2017‒11‒26
six papers selected by
Gavin McStay
New York Institute of Technology

  1. Cell. 2017 Nov 16. doi: 10.1016/j.cell.2017.10.036171(5):
    Abstract:  Transcription in human mitochondria is driven by a single-subunit, factor-dependent RNA polymerase (mtRNAP). Despite its critical role in both expression and replication of the mitochondrial genome, transcription initiation by mtRNAP remains poorly understood. Here, we report crystal structures of human mitochondrial transcription initiation complexes assembled on both light and heavy strand promoters. The structures reveal how transcription factors TFAM and TFB2M assist mtRNAP to achieve promoter-dependent initiation. TFAM tethers the N-terminal region of mtRNAP to recruit the polymerase to the promoter whereas TFB2M induces structural changes in mtRNAP to enable promoter opening and trapping of the DNA non-template strand. Structural comparisons demonstrate that the initiation mechanism in mitochondria is distinct from that in the well-studied nuclear, bacterial, or bacteriophage transcription systems but that similarities are found on the topological and conceptual level. These results provide a framework for studying the regulation of gene expression and DNA replication in mitochondria.
    Keywords:  Initiation; Initiation Complex; Mitochondria; POLRMT; Polymerase; TEFM; TFAM; TFB2M; Transcription
  2. Mol Cell. 2017 Nov 16. doi: 10.1016/j.molcel.2017.10.02968(4):
    Abstract:  Autophagy allows the degradation of cytosolic endogenous and exogenous material in the lysosome. Substrates are engulfed by double-membrane vesicles, coined autophagosomes, which subsequently fuse with lysosomes. Depending on the involvement of specific receptor proteins, autophagy occurs in a selective or nonselective manner. While this process is well understood at the level of bulky cargo such as mitochondria and bacteria, we know very little about individual proteins and protein complexes that are engulfed and degraded by autophagy. In contrast to the critical role of autophagy in balancing proteostasis, our current knowledge of the autophagic degradome is very limited. Here, we combined proximity labeling with quantitative proteomics to systematically map the protein inventory of autophagosomes. Using this strategy, we uncovered a basal, housekeeping mitophagy pathway that involves piecemeal degradation of mitochondrial proteins in a LC3C- and p62-dependent manner and contributes to mitochondrial homeostasis maintenance when cells rely on oxidative phosphorylation.
    Keywords:  APEX2; LC3C; MTX1; SQSTM1; autophagosomes; enzyme-based proximity labeling; human ATG8 family; mitophagy; p62; piecemeal degradation
  3. Mol Cell. 2017 Nov 16. doi: 10.1016/j.molcel.2017.10.02268(4):
    Abstract:  Vms1 translocates to damaged mitochondria in response to stress, whereupon its binding partner, Cdc48, contributes to mitochondrial protein homeostasis. Mitochondrial targeting of Vms1 is mediated by its conserved mitochondrial targeting domain (MTD), which, in unstressed conditions, is inhibited by intramolecular binding to the Vms1 leucine-rich sequence (LRS). Here, we report a 2.7 Å crystal structure of Vms1 that reveals that the LRS lies in a hydrophobic groove in the autoinhibited MTD. We also demonstrate that the oxidized sterol, ergosterol peroxide, is necessary and sufficient for Vms1 localization to mitochondria, through binding the MTD in an interaction that is competitive with binding to the LRS. These data support a model in which stressed mitochondria generate an oxidized sterol receptor that recruits Vms1 to support mitochondrial protein homeostasis.
    Keywords:  ROS signaling; S. cerevisiae; biochemistry; lipid signaling; liposomes; mitochondrial quality control; oxidative stress; protein degradation; sterols; structure-function
  4. Mol Cell. 2017 Nov 16. doi: 10.1016/j.molcel.2017.11.00368(4):
    Abstract:  Maintenance of mitochondrial function during stress conditions is vital for cellular survival. In this issue of Molecular Cell, Nielson et al. (2017) characterize a unique domain within Vms1 that allows this protein quality control component to specifically recognize damaged or stressed compartments within the mitochondrial network.
  5. Ann Neurol. 2017 Nov 17. doi: 10.1002/ana.25099
    Abstract:  In Parkinson's disease (PD), mitochondrial dysfunction associates with nigral dopaminergic neuronal loss. Cholinergic neuronal loss co-occurs, particularly within a brainstem structure, the pedunculopontine nucleus (PPN). We isolated single cholinergic neurons from post-mortem PPNs of aged controls and PD patients. Mitochondrial DNA (mtDNA) copy number and mtDNA deletions were increased significantly in PD patients compared to controls. Furthermore, compared to controls the PD patients had significantly more PPN cholinergic neurons containing mtDNA deletion levels exceeding 60%, a level associated with deleterious effects on oxidative phosphorylation. The current results differ from studies reporting mtDNA depletion in nigral dopaminergic neurons of PD patients. This article is protected by copyright. All rights reserved.
  6. Genome Biol Evol. 2017 Nov 14. doi: 10.1093/gbe/evx235
    Abstract:  Many bivalve species have two types of mitochondrial DNA (mtDNA) passed independently through the female line (F genome) and male line (M genome). Here we study the Cytochrome oxidase I (COI) protein in such bivalve species and provide evidence for differences between the F and M proteins in amino acid property values, particularly relating to hydrophobicity and helicity. The magnitude of these differences varies between different regions of the protein and the change from the ancestor is most marked in the M protein. The observed changes occur in parallel and in the same direction in the different species studied. Two possible causes are considered, first relaxation of purifying selection with drift and second positive selection. These may operate in different ways in different regions of the protein. Many different amino acid substitutions contribute in a small way to the observed variation but substitutions involving alanine and serine have a quantitatively large effect. Some of these substitutions are potential targets for phosphorylation and some are close to residues of functional importance in the catalytic mechanism. We propose that the observed changes in the F and M proteins might contribute to functional differences between them relating to ATP production and mitochondrial membrane potential with implications for sperm function.
    Keywords:  amino acid properties; bivalves; doubly uniparental inheritance; heteroplasmy; mtDNA; protein structure