bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2025–01–12
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Caspase Inhibition Restores Collagen I α1 and Fibronectin Release in Cigarette Smoke Extract-Exposed Human Lung Fibroblasts.
  2. COA5 has an essential role in the early stage of mitochondrial complex IV assembly.
  1. Am J Physiol Lung Cell Mol Physiol. 2025 Jan 08.
    Caspase Inhibition Restores Collagen I α1 and Fibronectin Release in Cigarette Smoke Extract-Exposed Human Lung Fibroblasts.
    Agnese La Mensa, Marco Buscetta, Roy R Woldhuis, Maura Cimino, Maria Rita Giuffrè, Marta Cristaldi, Paola Dino, Luigi Fiore, Alberto Fucarino, Giovanna Lo Iacono, Alessandro Bertani, Corry-Anke Brandsma, Fabio Bucchieri, Chiara Cipollina.
      Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by obstructed airflow, airway remodeling, and inflammation, with cigarette smoke (CS) exposure being the main risk factor. While CS extract (CSE) has been shown to activate caspases in various cell types, the role of caspases in human lung fibroblasts (hLFs), in COPD remains poorly understood. Recent studies have linked caspases to extracellular matrix (ECM) remodeling in skin and kidney fibrosis. Caspase activation can be triggered by oxidative stress, with active caspase-3 executing the pore-forming protein gasdermin E (GSDME) in the cleaved N-terminal form GSDME-NT. We investigated whether CSE activates caspases and GSDME in hLFs, and their role in ECM remodeling. MRC-5 lung fibroblasts were treated with CSE with or without the antioxidant N-acetyl cysteine (NAC), and the caspase-8 inhibitor z-IETD-fmk. We measured the effects on caspase-1-8-3/7 activation, GSDME cleavage, ECM remodeling (procollagen Iα1, COLIα1, and fibronectin, FN), and mitochondrial superoxide (mSOX) generation. Key findings were validated in patient-derived hLFs (phLFs). Our results showed that CSE induced caspase-1-8-3/7 activation, mSOX generation, and decreased COLIα1 and FN levels in MRC-5. CSE caused caspase-8-dependent activation of caspase-3, leading to the GSDME cleavage. Treatment with NAC inhibited mSOX and caspase activation. Inhibition of caspase-8 and mSOX restored FN and COLIα1 levels. In phLFs, we confirmed caspase-1 and -8 activation, mSOX increase, COLIα1/FN decrease, and the effects of NAC. Our findings highlight the role of the axis caspase-8-3/7-GSDME and mSOX in regulating ECM protein, suggesting that these pathways may contribute to remodeling in COPD.
    Keywords:  ECM; caspase; cigarette smoke extract; gasdermin E; human lung fibroblasts; lung remodeling
    DOI:  https://doi.org/10.1152/ajplung.00214.2024
  2. Life Sci Alliance. 2025 Mar;pii: e202403013. [Epub ahead of print]8(3):
    COA5 has an essential role in the early stage of mitochondrial complex IV assembly.
    Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie S Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor.
      Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.
    DOI:  https://doi.org/10.26508/lsa.202403013
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