16 Proteins localized on the mitochondrial outer membrane, including BNIP3L, BNIP3, and FUNDC1 (FUN14 domain containing 1), are specific receptors for mitophagic recognition during red blood cell maturation, metabolic stress, and hypoxia.
Mitophagy is a highly conserved mechanism of selectively delivering unwanted mitochondria for lysosomal degradation.
Markly photohsop series#
16 Hence, orchestrated mitochondrial biogenesis, dynamics, and degradation by mitophagy constitute a series of quality control measures to prevent the accumulation of damaged mitochondria and excessive ROS production.
15 In case of more extensive damage, segregation of irreversibly damaged mitochondria through fission is a prerequisite for appropriate engulfment and degradation via mitochondria selective autophagy known as mitophagy. 13,14 Fusion has been shown to rescue damaged mitochondria by redistributing proteins and by maintaining mitochondrial DNA integrity. Mitochondrial quality is maintained via the optimal balance between biogenesis and degradation for renewal, and mitochondria are also highly dynamic organelles undergoing continuous fusion and fission cycles. 3,10 Mitochondrial respiratory chain dysfunction accompanying enhanced ROS production can be attributed to cigarette smoke (CS) exposure, a main cause for COPD development. 2, 4-9 Although the molecular mechanism underlying cell senescence regulation is still unknown, reactive oxygen species (ROS) released during mitochondrial respiration has been generally implicated in the progression of cellular senescence. 1-3 Recent advances COPD have implicated acceleration of cell senescence in both alveolar and airway epithelial cells, which is functionally characterized by impaired cell regeneration and aberrant cytokine secretion of the senescence-associated secretory phenotype (SASP), in COPD pathogenesis. Reduced PARK2 expression levels in COPD lung suggest that insufficient mitophagy is a part of the pathogenic sequence of COPD.Īdvanced age is one of the most important risk factors for development of chronic obstructive pulmonary disease (COPD) and an increased number of senescent cells is a major feature of aging. These results suggest that PINK1-PARK2 pathway-mediated mitophagy plays a key regulatory role in CSE-induced mitochondrial ROS production and cellular senescence in HBEC. Evaluation of protein levels demonstrated decreased PARK2 in COPD lungs compared with non-COPD lungs. CSE-induced mitophagy was inhibited by PINK1 and PARK2 knockdown, resulting in enhanced mitochondrial ROS production and cellular senescence in HBEC. We demonstrated that CSE-induced mitochondrial damage was accompanied by increased ROS production and HBEC senescence. PINK1 and PARK2 protein levels in lungs from patients were evaluated by means of lung homogenate and immunohistochemistry. To elucidate the involvement of PINK1 and PARK2 in mitophagy, knockdown and overexpression experiments were performed. Mitophagy was assessed in BEAS-2B cells stably expressing EGFP-LC3B, using confocal microscopy to measure colocalization between TOMM20-stained mitochondria and EGFP-LC3B dots as a representation of autophagosome formation. Mitochondrial damage, ROS production, and cell senescence were evaluated in primary human bronchial epithelial cells (HBEC). Therefore, we sought to investigate to determine if PINK1-PARK2-mediated mitophagy is involved in the regulation of CS extract (CSE)-induced cell senescence and in COPD pathogenesis. Mitophagy may play a pivotal role for removal of CS-induced damaged mitochondria, and the PINK1 (PTEN-induced putative kinase 1)-PARK2 pathway has been proposed as a crucial mechanism for mitophagic degradation. Cigarette smoke (CS)-induced mitochondrial damage with increased reactive oxygen species (ROS) production has been implicated in COPD pathogenesis by accelerating senescence.
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