Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

Abstract

Myriad forms of endogenous and environmental stress disrupt mitochondrial function by impacting critical processes in mitochondrial homeostasis, such as mitochondrial redox system, oxidative phosphorylation, biogenesis, and mitophagy. External stressors that interfere with the steady state activity of mitochondrial functions are generally associated with an increase in reactive oxygen species, inflammatory response, and induction of cellular senescence (inflammaging) potentially via mitochondrial damage associated molecular patterns (DAMPS). Many of these are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) and its exacerbations. In this review, we highlight the primary mitochondrial quality control mechanisms that are influenced by oxidative stress/redox system, including role of mitochondria during inflammation and cellular senescence, and how mitochondrial dysfunction contributes to the pathogenesis of COPD and its exacerbations via pathogenic stimuli.

Keywords: Cellular senescence; DAMPs; Inflammation; Mitophagy; Oxidative phosphorylation; Redox; Telomere.

Figure 1. Mitochondrial function maintained by mitophagy

Reduced mitochondrial membrane potential in Parkin competent cells stimulates Drp1 fission. A) Homeostasis: In cells unchallenged by excessive stress, fission and fusion occurs at basal level. Most mitochondria are polarized and maintain Pink1 import into the inner mitochondrial membrane. B) Stress: Substantial loss of mitochondrial membrane potential promotes fission. Pink1 stabilization on the outer membrane (OM) recruits the E3 ligase Parkin. The E3 ligase Gp78 which is associated with smooth endoplasmic reticulum membranes is activated independently of Parkin to promote fission. Both Parkin and Gp78 potentiates the degradation of mitochondrial fusion proteins mitofusin 1 and mitofusin 2 (MFN 1/2). AMPK activates mitochondrial fission factor (MFF) to recruit Drp1 mediates membrane “constriction” at the site of fission through its GTPase activity. MARCH5 is a mitochondrial E3 Ligase that promotes Drp1 along with Fis1 and mid51. Parkin also catalyzes the ubiquitination of OM mitochondrial proteins. Pink1 phosphorylates ubiquitin leading to Parkin activation which is involved in the mitophagy induction process. C) Mitophagy: Depolarized mitochondria are unable to fuse back into the function pool of mitochondria. Scaffolding protein p62 binds to OM ubiquitin in addition to Smurf1, and Nix, to facilitate mitochondria targeting to LC3b coated autophagosomes.

Figure 2. Mitochondrial stress mediated mitochondrial derived vesicle (MDV) formation and activates inflammasome

A) Prior to mitophagy, oxidative stress and loss of mitochondrial membrane potential recruits Parkin to mediate mitochondrial derived vesicle (MDV) formation. MDVs load oxidized protein and lipid constituents for delivery into the lysosome. MDVs are mitochondrial derived cargos that contain selective proteins involved in electron transport chain (ETC). Oxidized lipids and ETC proteins of complexes II, III, and IV are targeted for MDV mediated degradation. B) During mitochondrial stress, damage to mitochondria can lead to calcium influx and opening of the mitochondrial permeability transition pore (MPTP). Opening of MPTP is correlated with release of mitochondrial mtDNA. Oxidized mtDNA binds to the Nlrp3 inflammasome interacting with mitochondrial derived cardiolipin (CL). This stimulates its activation and release of inflammatory mediators IL1-β and IL-18. Inflammasome is also able to promote pyroptosis, a highly inflammatory type of cell death. Pyroptosis occurs through Caspase-1 mediated events which may further amplify release of inflammatory damage associated molecular patterns (DAMPS) and perpetuate inflammation throughout the tissue. Released ATP acts as a DAMP through purinergic receptor signaling (P2X/Y) and transactivates NFκB expression further enhancing inflammasome activation. Extracellular mtDNA released from damaged cells or may be enclosed in exosomes bind to and stimulate Toll-like receptor (TLR) signaling to Nlrp3. These pattern recognition receptors PRRs integrate extracellular damage signals that converge on mitochondrial mediated inflammatory response. DNase II has a role in regulating Nlrp3 signaling and through mtDNA digestion. Oxidized lipids, ETC proteins and mtDNA are marked in red color with “X” symbol.

Figure 3. Elongation of mitochondria as a survival mechanism

Perinuclear enrichment of elongated mitochondria under different stress responses, allows cell survival when mitophagy is disrupted. It is thought this stress response potentially protects a portion of mitochondria against excessive mitophagy. A) Cigarette smoke exposure impairs Parkin translocation to mitochondria which is associated with impaired mitophagy while promoting increased levels of fusion protein Mfn2 and a reduction in fission protein Drp1. Parkin may not be able to promote fission by potentiating Mfn2 degradation. B) Ultraviolet light, Cyclohexamide, and Actinomycin D induced mitochondrial elongation is a SLP-2 dependent manner. Stabilization of SLP-2 on the outer mitochondrial membrane following stress, results in stabilization of the long form Opa1 fusion protein. C) Nutrient starvation activates Protein Kinase A to phosphorylate fission protein Drp1 and inhibit its activity. AMPK has been shown to promote Drp1 activity which may involve regulation by PKA and Sirt1 activity. During starvation induced stress, AMPK promotes NAD⁺ levels which can function to enhance AMPK by Sirt1 mediated deacetylation. Evidence that PKA can also block AMPK activity as well suggests a hypothetically a level of control may occur here to promote the ideal amount of mitochondrial fusion and elongation. Elongation following starvation upholds ATP production in the cell by maintaining membrane potential and hence elongated mitochondria appear to be resistant to mitophagy.

Figure 4. Cigarette smoke-mediated mitochondrial dysfunction is due to impaired mitophagy leading to cellular senescence in COPD

This schematic is based on our recent report that CS-induced oxidative stress causes reduction in cellular ATP levels and increase in ROS along with mitochondrial dysfunction thereby activating Pink1-Parkin mediated mitochondrial fusion (Mfn2) leading to perinuclear clustering of dysfunctional mitochondria (elongated). This process is accompanied by increase in DNA damage-initiated cellular senescence. Cigarette smoke exposure affects Parkin and p53 interaction, as a result impairs Parkin-dependent mitophagy process and increases perinuclear mitochondrial clustering. Mitophagy impairment and cellular senescence phenotype was considerably rescued by Parkin overexpression along with MitoT treatment. This observation supports the notion that molecular mechanisms of mitophagy play an essential role during CS stress-induced cellular senescence via suborganellar signaling in COPD.

Figure 5. Mitochondrial Stress in COPD

Inflammation is strongly associated with progressive lung diseases such as chronic obstructive pulmonary disease (COPD). Healthy lung: There are over 40 different lung cell types including infiltrating leukocytes that maintain tissue homeostasis. Lung parenchymal and immune cell communication in response to endogenous or environmental stress (bacterial and viral infections, smoking, air pollution) relay inflammatory signals between each other. The inflammatory signals that are critical to tissue repair and pathogen defenses achieve resolution from an inflammatory state and retain respiratory function. Inflamed lung: In lung disease, respiration is comprised in chronic and progressive chronic lung diseases (COPD). Mitochondria are central in mediating respiration and recent findings support that mitochondrial stress and dysfunction correlates with chronic airway diseases. This schematic introduces mitochondrial stress and dysfunction plays a key role in the inflammatory state associated with chronic lung diseases. Oxidative stress causes release of damage associated molecular patterns (DAMPS) from dysfunctional mitochondria and damaged cells. The contributing role of exosomes in the pathogenesis of chronic lung diseases is an emerging theme that needs to be explored. Together, the chronic mitochondrial stress would enable a vicious cycle that relentlessly promotes disease state (tissue remodeling, inflammatory cellular influx, senescence, susceptibility to infection). Current anti-inflammatory regimens do little to reverse disease progression. This may be due to the persistence of inflammatory signaling by abnormal mitochondria. Therefore, therapies that effectively target and improve mitochondrial function throughout the lung might be critical in taking steps towards blocking damaging inflammatory processes including exacerbations that further harm the tissue.