Mitochondrial Dysfunction and Metabolic Regulation of the Necroptosis Pathway in COPD and IPF

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Abstract Fibrosis and emphysema represent divergent clinical phenotypes that emerge during the pathogenesis of chronic lung diseases induced by cigarette smoke (CS). We have uncovered Udistinct mitochondrial and metabolic pathways in response to injurious stimuli that may underlie divergent pathways leading to fibrosis or emphysema outcomesU. Mitochondria are key organelles that regulate metabolism and energy generation, with complex processes governing their dynamics (fusion, fission), and turnover (mitophagy). Mitochondrial dysfunction is an emerging mechanism underlying the pathogenesis of many human diseases including COPD and IPF. We have demonstrated that mitochondrial dysfunction mediates CS-induced epithelial cell injury/emphysema development, and bleomycin (BLM)-induced pulmonary fibrosis; and interestingly, that genetic deficiency in the critical mitophagy regulator PTEN-induced putative kinase-1 (PINK1) is UprotectiveU in preclinical models of CS- induced emphysema while UdeleteriousU in BLM-induced pulmonary fibrosis. Moreover, PINK1-dependent mitophagy was linked to the activation of receptor-interacting protein kinase-3 (RIPK3), a key signaling kinase mediating regulated necrosis (necroptosis). We have published that RIPK3 regulates metabolic processes in organ tissue, including (FA) biosynthetic pathways, and observed that genetic deficiency in fatty acid synthase (FASN), aggravated pulmonary fibrosis. Interestingly, we have found that CS-induced lung injury may trigger systemic responses including injury to distal organs (kidney). Moreover, we and others have found that circulating cell-free (cf)-mtDNA, an established marker of mitochondrial injury and dysfunction, is regulated in plasma or urine of COPD and IPF patients, and that cf-mtDNA sequence variability (heteroplasmy) may play critical roles in the pathogenesis of lung diseases. These intriguing data suggest that mitochondrial pathways influence functional and clinical phenotypes (fibrosis vs. emphysema) in response to CS exposure and led us to propose the following Uhypotheses:U Mitochondrial dysfunction in response to CS can regulate pathways leading to divergent phenotype in COPD or IPF, including the activation of PINK-dependent mitophagy and downstream regulation of RIPK3. Furthermore, key metabolic and mitochondrial signals including mitochondrial fusion/fission and lipid metabolism may determine cellular pathways leading to emphysema or fibrosis. Plasma and/or urinary cf-mtDNA, as well as degree of mitochondrial heteroplasmy, may correlate with severity of IPF and COPD. We will address our hypotheses in the following USpecific Aims:U Specific Aim 1: To determine the functional significance of PINK1-regulated RIPK3 signaling in experimental emphysema and fibrosis. Specific Aim 2: To determine the mechanism(s) by which mitochondrial and metabolic pathways regulate PINK1-RIPK3 signaling in experimental emphysema and fibrosis. Specific Aim 3: To evaluate whether circulating or urinary cf-mtDNA is associated with severity of disease in IPF and COPD.