The possible links between COPD and lung cancer: cellular and mitochondrial function in airway epithelial cells

Cigarette smoke (CS) is a major risk factor for both COPD and lung cancer and many lung cancer patients have COPD. CS-derived oxidant exposure in airway epithelial cells leads to abnormal function. Persistent inflammation in COPD together with mutations and dysregulated cell cycle contributes to lung cancer development. Mitochondria are the hub of bioenergetics, reactive oxygen species (ROS) production and intracellular signalling pathways. The role of mitochondria in the development of lung cancer in COPD is not widely investigated. We hypothesised that mitochondrial dysfunction causes some COPD patients to develop lung cancer. Treatment of bronchial epithelial cell line (BEAS-2B) with hydrogen peroxide (H2O2) caused mitochondrial function alteration and apoptosis. Interleukin (IL)-1β-induced proliferation and inflammation was greater when co-treated with H2O2. N-acetyl cysteine had a greater protective effect than mitochondrial-targeted antioxidants. The effects of mitochondrial-directed antioxidants were also investigated in BEAS-2B, normal primary bronchial epithelial cells (NHBE) and the lung cancer cell line (A549). At baseline, A549 showed lower mitochondrial membrane potential and higher mitochondrial superoxide and respiration spare capacity. Mitochondrial protection by antioxidants in these cell types was unclear as H2O2 minimally affected the mitochondrial parameters and cell functions. Gene Set Variation Analysis (GSVA) revealed that oxidative phosphorylation (OXPHOS) and glycolysis pathway signatures in lung cancer patients were related to smoking status. Matched normal-tumour pairs showed significantly higher glycolytic gene expression in tumour whereas higher mitochondrial protein (NDUFA9) expression was detected in background tissue from smokers compared with tumour tissue in COPD patients suggesting an early OXPHOS compensatory mechanism in background tissue and glycolytic switching in the tumour. Background and tumour tissues suggested defects in mitochondrial structure in COPD. This study provides an initial insight into how changes in mitochondria and metabolic pathways could link COPD and lung cancer and has clinical implications for carcinogenesis prevention by treating COPD patients.Open Acces

Mitochondria-targeted hydrogen sulfide delivery molecules protect against uva-induced photoaging in dermal fibroblasts, and in mouse skin in vivo

Aims Oxidative stress and mitochondrial dysfunction play a role in the process of skin photoaging via activation of matrix metalloproteases (MMPs) and the subsequent degradation of collagen. The activation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor controlling antioxidant and cytoprotective defense systems, might offer a pharmacological approach to prevent skin photoaging. We therefore investigated might offer a pharmacological approach to prevent skin photoaging. We therefore investigated protective effect of the novel mitochondria-targeted hydrogen sulfide (H(2)S) delivery molecules AP39 and AP123, and non-targeted control molecules on UVA-induced photoaging in normal human dermal fibroblasts (NDHFs) in vitro and the skin of BALB/c mice in vivo. Results In NDHFs AP39 and AP123 (50-200 nM) but not non-targeted controls suppressed UVA (8 J/cm2)-mediated cytotoxicity and induction of MMP-1 activity, preserved cellular bioenergetics and increased the expression of collagen and nuclear levels of Nrf2. In in vivo experiments, topical application of AP39 or AP123 (0.3-1 µM/cm(2); but not non-targeted control molecules) to mouse skin prior to UVA (60 J/cm(2)) irradiation prevented skin thickening, MMP induction, collagen loss oxidative stress markers 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased Nrf2-dependent signaling as well as increased manganese superoxide dismutase (MnSOD) levels and levels of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-gamma coactivator (PGC-1?). Innovation and Conclusion Targeting H(2)S delivery to mitochondria may represent a novel approach for the prevention and treatment of skin photoaging, as well as being useful tools for determining the role of mitochondrial H(2)S in skin disorders and aging.Not heldPublished version, accepted version (12 month embargo