bims-resufa Biomed News
on Respiratory supercomplex factors
Issue of 2025–02–16
two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Saccharomyces cerevisiae Dmo2p is required for the stability and maturation of newly translated Cox2p.
  2. The Supramolecular Architecture of Mitochondrial Complex I in the Rat Brain Is Altered by Alzheimer's-Like Cerebral Amyloidosis.
  1. FEBS J. 2025 Feb 11.
    Saccharomyces cerevisiae Dmo2p is required for the stability and maturation of newly translated Cox2p.
    Maria Antônia Kfouri Martins Soares, Letícia Veloso Ribeiro Franco, Jhulia Almeida Clarck Chagas, Fernando Gomes, Mário H Barros.
      Based on available platforms detailing the Saccharomyces cerevisiae mitochondrial proteome and other high-throughput studies, we identified the yeast gene DMO2 as having a profile of genetic and physical interactions that indicate a putative role in mitochondrial respiration. Dmo2p is a homologue to human distal membrane-arm assembly complex protein 1 (DMAC1); both proteins have two conserved cysteines in a Cx2C motif. Here, we localised Dmo2p in the mitochondrial inner membrane with the conserved cysteines facing the intermembrane space. The respiratory deficiency of dmo2 mutants at 37°C led to a reduction in cytochrome c oxidase (COX) activity (COX) and in the formation of cytochrome bc1 complex-COX supercomplexes; dmo2 also has a rapid turnover of Cox2p, the second subunit of the COX complex that harbours the binuclear CuA centre. Moreover, Dmo2p co-immunoprecipitates with Cox2p and components required for maturation of the CuA centre, such as Sco1p and Sco2p. Finally, DMO2 overexpression can suppress cox23 respiratory deficiency, a mutant that has impaired mitochondrial copper homeostasis. Mass spectrometry data unveiled the interaction of Dmo2p with different large molecular complexes, including bc1-COX supercomplexes, the TIM23 machinery and the ADP/ATP nucleotide translocator. Overall, our data suggest that Dmo2p is required for Cox2p maturation, potentially by aiding proteins involved in copper transport and incorporation into Cox2p.
    Keywords:  COX assembly; CuA site formation; DMAC1 homologue
    DOI:  https://doi.org/10.1111/febs.70009
  2. J Neurochem. 2025 Feb;169(2): e70017
    The Supramolecular Architecture of Mitochondrial Complex I in the Rat Brain Is Altered by Alzheimer's-Like Cerebral Amyloidosis.
    Gisela V Novack, Pablo Galeano, Lucas A Defelipe, Lorenzo Campanelli, Karen S Campuzano, Cecilia Rotondaro, Eduardo M Castaño, Sonia Do Carmo, A Claudio Cuello, María M García-Alai, Laura Morelli.
      Mitochondrial respiratory complexes are organized into supercomplexes (SC) to regulate electron flow and mitigate oxidative stress. Alterations in SC organization in the brain may affect energy expenditure, oxidative stress, and neuronal survival. In this report, we investigated the amount, activity and organization of mitochondrial complex I (CI) in the hippocampus of 12-month-old McGill-R-Thy1-APP transgenic (Tg) rats, an animal model of Alzheimer's-like cerebral amyloidosis. By means of BN-PAGE, we found that the organization of SC did not differ between genotypes, but a lower abundance of SC was detected in Tg compared to wild-type (WT) rats. Using a more sensitive technique (2-D electrophoresis followed by Western blot), higher levels of free CI and a decrease in the relative abundance of assembled CI in SC (I-III2 and I-III2-IV) were observed in Tg rats. In-gel activity assays showed that the total activity of CI (CI + SC-CI) is lower in Tg compared to WT, while Tg samples show a significant decrease in SC-CI-associated activity. This alteration in CI assembly was associated with nitro-oxidative stress and changes in mitochondrial fusion-fission parameters. To assess CI composition, we applied LC-MS/MS to the isolated CI from BN-PAGE and found that 11 of 45 subunits described in mammals were found to be less abundant in Tg. We examined the levels of the nuclear-derived NDUFA9 subunit, which is critical for CI assembly, and found higher levels in the cytoplasmic fraction and lower levels in the mitochondrial fraction in Tg, suggesting that brain amyloidosis affects the import of CI subunits from the cytosol to the mitochondria, destabilizing the SC. This is the first report to characterize the types, abundance and activity of SC in the hippocampus of an animal model of cerebral amyloidosis, providing additional experimental evidence for the molecular mechanisms underlying the brain bioenergetic deficit characteristic of Alzheimer's disease.
    Keywords:  OXPHOS; mitochondria; native electrophoresis; neurodegeneration; nitroxidative stress; supercomplexes
    DOI:  https://doi.org/10.1111/jnc.70017
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