bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2019–01–27
six papers selected by
Gavin McStay, Staffordshire University
  1. The relevance of the supramolecular arrangements of the respiratory chain complexes in human diseases and aging.
  2. Aggregation of Respiratory Complex Subunits Marks the Onset of Proteotoxicity in Proteasome Inhibited Cells.
  3. Diagnosis of 'possible' mitochondrial disease: an existential crisis.
  4. [The underestimated coding potential of mitochondrial DNA].
  5. Mitochondrial Proteolysis and Metabolic Control.
  6. The yeast mitochondrial proteins Rcf1 and Rcf2 support the enzymology of the cytochrome c oxidase complex and generation of the proton motive force.
  1. Mitochondrion. 2019 Jan 18. pii: S1567-7249(17)30317-3. [Epub ahead of print]
    The relevance of the supramolecular arrangements of the respiratory chain complexes in human diseases and aging.
    I Ramírez-Camacho, O Flores-Herrera, C Zazueta.
      Mitochondrial dysfunction, a common factor in several diseases is accompanied with reactive oxygen species (ROS) production. These molecules react with proteins and lipids at their site of generation, establishing a vicious cycle which might result in further mitochondrial injury. It is well established that mitochondrial respiratory complexes can be organized into supramolecular structures called supercomplexes (SCs) or respirasomes; yet, the physiological/pathological relevance of these structures remains unresolved. Changes in their stabilization and content have been documented in Barth's syndrome, degenerative diseases such as Parkinson's and Alzheimer, cardiovascular diseases including heart failure and ischemia-reperfusion damage, as well as in aging. Under pathological conditions, SCs stability could have relevant biomedical implications or might be used as a reliable marker of mitochondrial damage. The purpose of this review is to recapitulate the current state of the significance on mitochondrial bioenergetics of these structures and their possible role in pathophysiologies related with ROS increase.
    Keywords:  Aging; Alzheimer's disease; Barth Syndrome; Heart failure; Ischemia-reperfusion; Parkinson; Respiratory chain supercomplexes
    DOI:  https://doi.org/10.1016/j.mito.2019.01.001
  2. J Mol Biol. 2019 Jan 22. pii: S0022-2836(19)30031-2. [Epub ahead of print]
    Aggregation of Respiratory Complex Subunits Marks the Onset of Proteotoxicity in Proteasome Inhibited Cells.
    Shivali Rawat, Valpadashi Anusha, Manoranjan Jha, K Sreedurgalakshmi, Swasti Raychaudhuri.
      Proteostasis is maintained by optimal expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers protein aggregation and is implicated in many age-related pathologies. In this study, using quantitative proteomics and microscopy, we show that aggregation of many nuclear-encoded mitochondrial proteins is an early protein-destabilization event during short-term proteasome inhibition. Among these, Respiratory Chain Complex (RCC) subunits represent a group of functionally related proteins consistently forming aggregates under multiple proteostasis-stresses with varying aggregation-propensities. Sequence analysis reveals that several RCC subunits, irrespective of the cleavable mitochondrial targeting sequence (MTS), contain low complexity regions (LCR) at the N-terminus. Using different chimeric and mutant constructs, we show that these low complexity regions partially contribute to the intrinsic instability of multiple RCC subunits. Taken together, we propose that physicochemically driven aggregation of unassembled RCC subunits destabilizes their functional assembly inside mitochondria. This eventually deregulates the biogenesis of respiratory complexes and marks the onset of mitochondrial dysfunction.
    Keywords:  Low complexity region; Mitochondria; Mitochondrial respiratory chain complex; Protein aggregation; Protein misfolding; Protein turnover; Proteomics; Proteostasis
    DOI:  https://doi.org/10.1016/j.jmb.2019.01.022
  3. J Med Genet. 2019 Jan 25. pii: jmedgenet-2018-105800. [Epub ahead of print]
    Diagnosis of 'possible' mitochondrial disease: an existential crisis.
    Sumit Parikh, Amel Karaa, Amy Goldstein, Enrico Silvio Bertini, Patrick F Chinnery, John Christodoulou, Bruce H Cohen, Ryan L Davis, Marni J Falk, Carl Fratter, Rita Horvath, Mary Kay Koenig, Michaelangelo Mancuso, Shana McCormack, Elizabeth M McCormick, Robert McFarland, Victoria Nesbitt, Manuel Schiff, Hannah Steele, Silvia Stockler, Carolyn Sue, Mark Tarnopolsky, David R Thorburn, Jerry Vockley, Shamima Rahman.
      Primary genetic mitochondrial diseases are often difficult to diagnose, and the term 'possible' mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. In instances when a genetic diagnosis cannot be confirmed, a diagnosis of 'possible' mitochondrial disease may result in harm to patients and their families, creating anxiety, delaying appropriate diagnosis and leading to inappropriate management or care. A categorisation of 'diagnosis uncertain', together with a specific description of the metabolic or genetic abnormalities identified, is preferred when a mitochondrial disease cannot be genetically confirmed.
    Keywords:  clinical genetics; diagnosis; evidence based practice; metabolic disorders
    DOI:  https://doi.org/10.1136/jmedgenet-2018-105800
  4. Med Sci (Paris). 2019 Jan;35(1): 46-54
    [The underestimated coding potential of mitochondrial DNA].
    Annie Angers, Philip Ouimet, Assia Tsyvian-Dzyabko, Tanya Nock, Sophie Breton.
      Mitochondria are ancient organelles that emerged from the endosymbiosis of free-living proto-bacteria. They still retain a semi-autonomous genetic system with a small genome. Mitochondrial DNA (mtDNA) codes for 13 essential proteins for the production of ATP, the sequences of which are relatively conserved across Metazoans. The discovery of additional mitochondria-derived peptides (MDPs) indicates an underestimated coding potential. Humanin, an anti-apoptotic peptide, is likely independently transcribed from within the 16S rRNA gene, as are recently described SHLPs. MOTS-c, discovered in silico, has been demonstrated to be involved in metabolism and insulin sensitivity. Gau, is a positionally conserved open reading frame (ORF) sequence found in the antisense strand of the COX1 gene and its corresponding peptide is strictly colocalized with mitochondrial markers. In bivalves with doubly uniparental inheritance of mtDNA, male and female mtDNAs each carry a separate additional gene possibly involved in sex determination. Other MDPs likely exist and their investigation will shed light on the underestimated functional repertoire of mitochondria.
    DOI:  https://doi.org/10.1051/medsci/2018308
  5. Cold Spring Harb Perspect Biol. 2019 Jan 22. pii: a033936. [Epub ahead of print]
    Mitochondrial Proteolysis and Metabolic Control.
    Sofia Ahola, Thomas Langer, Thomas MacVicar.
      Mitochondria are metabolic hubs that use multiple proteases to maintain proteostasis and to preserve their overall quality. A decline of mitochondrial proteolysis promotes cellular stress and may contribute to the aging process. Mitochondrial proteases have also emerged as tightly regulated enzymes required to support the remarkable mitochondrial plasticity necessary for metabolic adaptation in a number of physiological scenarios. Indeed, the mutation and dysfunction of several mitochondrial proteases can cause specific human diseases with severe metabolic phenotypes. Here, we present an overview of the proteolytic regulation of key mitochondrial functions such as respiration, lipid biosynthesis, and mitochondrial dynamics, all of which are required for metabolic control. We also pay attention to how mitochondrial proteases are acutely regulated in response to cellular stressors or changes in growth conditions, a greater understanding of which may one day uncover their therapeutic potential.
    DOI:  https://doi.org/10.1101/cshperspect.a033936
  6. J Biol Chem. 2019 Jan 25. pii: jbc.RA118.006888. [Epub ahead of print]
    The yeast mitochondrial proteins Rcf1 and Rcf2 support the enzymology of the cytochrome c oxidase complex and generation of the proton motive force.
    Vera Strogolova, Ngoc H Hoang, Jonathan Hosler, Rosemary A Stuart.
      The yeast mitochondrial proteins Rcf1 and Rcf2 are associated with a subpopulation of the cytochrome bc 1-cytochrome c oxidase supercomplex and have been proposed to play a role in the assembly and/or modulating the activity of the cytochrome c oxidase (complex IV, CIV). Yeast mutants deficient in either Rcf1 or Rcf2 proteins can use aerobic respiration-based metabolism for growth, but the absence of both proteins results in a strong growth defect. In the present study, using assorted biochemical and biophysical analyses of Rcf1/Rcf2 single and double null-mutant yeast cells and mitochondria, we further explored how Rcf1 and Rcf2 support aerobic respiration and growth. We show that the absence of Rcf1 physically reduces the levels of CIV and diminishes the  ability of the CIV that is present to maintain a normal mitochondrial proton motive force (PMF). Although the absence of Rcf2 did not noticeably affect the physical content of CIV, the PMF generated by CIV was also lower than normal. Our results indicate that the detrimental effects of the absence of Rcf1 and Rcf2 proteins on the CIV complex are distinct in terms of CIV assembly/accumulation and additive in terms of the ability of CIV to generate PMF. Thus, the combined absence of Rcf1 and Rcf2 alters both CIV physiology and assembly. We conclude that the slow aerobic growth of the Rcf1/Rcf2 double null mutant results from diminished generation of mitochondrial PMF by CIV, and limits the level of CIV activity required for maintenance of the PMF and growth in aerobic conditions.
    Keywords:  OXPHOS; Rcf1/Rcf2; bioenergetics; cytochrome oxidase; mitochondria; mitochondrial respiratory chain complex; proton motive force
    DOI:  https://doi.org/10.1074/jbc.RA118.006888
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