Mitochondria in lung diseases

Abstract

Mitochondria are autonomous cellular organelles that oversee a variety of functions such as metabolism, energy production, calcium buffering and cell fate determination. Regulation of their morphology and diverse activities beyond energy production are being recognized as playing major roles in cellular health and dysfunction. This review is aimed at summarizing what is known regarding mitochondrial contributions to pathogenesis of lung diseases. Emphasis is given to understanding the importance of structural and functional aspects of mitochondria in both normal cellular function (based on knowledge from other cell types) and in development and modulation of lung diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Emerging techniques that allow examination of mitochondria, and potential strategies to target mitochondria in the treatment of lung diseases are also discussed.

Keywords::

• airway
• apoptosis
• autophagy
• fission
• fusion
• mitochondria
• oxidative stress
• proliferation
• reactive oxygen species

Financial & competing interests disclosure

The authors were Supported by Young Clinical Scientist Award (Aravamudan) and Clinician Investigator Award (Pabelick) from the Flight Attendants Medical Research Institute (FAMRI) and grants from the National Institutes of Health (R01 HL088029, HL056470 (Prakash) and HL090595 (Pabelick)). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Mitochondrial structure, dynamics and interactions with other organelles are tightly linked to their functional role in supplying cells with energy and signaling molecules, and in determining cellular fate.

• • Changes in mitochondrial morphology, manifested as fragmented or fused appearance, are not only indicators of mitochondrial stress, but they also correlate well with the metabolic efficiency of the mitochondrion and the resultant ROS production, integrity of mitochondrial membranes and the subsequent choice of the cell to survive or to go into apoptosis.

• • Though considerable progress has been made with regard to the regulation of fission and fusion, mitochondrial movement and interactions and reactive oxygen species (ROS) generation, the relevance of these phenomena to airway function and dysfunction/diseases is not as widely recognized as it is in other paradigms. However, available data suggest that mitochondria contribute significantly to chronic airway ailments (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), polycyclic aromatic hydrocarbon, etc), and that manipulations that restore mitochondrial function and/or mitochondrially regulated cellular equilibriums ameliorate disease symptoms.

• • Integration of data from studies on non-airway tissues will be of paramount importance, as mitochondrial sensitivities, and responses to cellular environments in the airway are comparable with those in other organs. This is likely to not only provide us with mechanistic insights on balanced/normal mitochondrial function in the airway, but also help us improvise methodologies for further analyses, diagnoses and therapeutic interventions.

• • Recent emergence of state-of-the-art imaging and quantification techniques, in combination with cell and molecular biological tools, and bioinformatics, has enabled live studies on mitochondria. While a contiguous evolution of this process is to be expected, our current understanding of the genomic complement and the metabolic processes in the mitochondria, and how they relate to cellular and organismal physiology, is taking shape more vividly. Thus, factors like signaling pathway components, regulators of ROS production and scavenging, cell cycle/apoptosis participants are targeted for drug development.

Notes