B. Functional Role of Mitochondria in Inflammation and Innate Immunity

During four billion years of evolution, prokaryotes have never been evolved to achieve morphological complexity beyond the rudimentary form. All complex organism is composed of eukaryotic cells. Why is that? A school of evolutionary biologists argue that the origin of mitochondria and the eukaryotic cell was plausibly the same event, which arose from prokaryotes just once four billion years ago via endosymbiosis; and, the acquisition of mitochondria was the critical step towards the origin of eukaryotes (Lane, 2015; Lane and Martin, 2010). In other words, the acquisition of mitochondria was prerequisite to eukaryote complexity and the key innovation en route to the development of multicellular life. Given this evolutionary history, it is no wonder that mitochondrial functions are inseparably integrated with fundamental cellular physiology, and thus, mitochondria are connected to every aspect of inflammatory and innate immune responses to keep cellular or organismal physiology in homeostasis. The functional role of mitochondria in association with chronic inflammation and its related disorders is summarized below, focusing on recently emerged conceptual advances (Figure 1).

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Figure 1

Role of mitochondria in the pathogenesis of chronic inflammatory disorders. A schematic diagram is illustrated to depict pathogenic roles of mitochondrial dysfunction which contribute to the development of multiple chronic inflammatory disorders. Mitochondrial physiology is integrated with fundamental biologic functions at the cellular level. When the mitochondrial physiology is perturbed, dysfunctional mitochondria instigate or propagate inappropriate and persistent inflammation via multiple mechanisms including inflammasomes activation, dysregulation of immune signaling, alteration of immunometabolism and the release of mitochondrial damage-associated molecular patterns (DAMPs), which, in consequence, lead to chronic inflammatory disorders in affected organs or systematically.

C. Mitochondrial DAMPs in Inflammation/ Innate Immunity

Given the evolutionary history, it is not surprising that mitochondria can work as a double-edged sword in regulating innate immune and inflammatory responses. The innate immune system evolved to recognize conserved bacterial molecules that are largely foreign to host cells. As mitochondria are considered to have originated from α-proteobacteria through endosymbiosis (Archibald, 2015), many similarities exist between mitochondrial and bacterial constituents. Thus, it has been hypothesized that mitochondrial constituents might play as damage-associated molecular patterns (DAMPs) that could trigger innate immune responses during pathological insults (Krysko et al., 2011). In other words, when mitochondria are stressed or functionally impaired, they may produce a variety of mitochondrial DAMPs which function as drivers of the inflammatory responses, and in certain situation could be pathologic. Recent information is summarized about mitochondrial DAMPs which are being actively studied in inflammation and inflammatory disorders (Figure 1).

D. Role of Mitochondrial in Immunometabolism

Different immune cells should adopt distinct metabolic configurations to balance its requirements for energy and molecular biosynthesis as they respond to immunological challenges. As a natural consequence, immunometabolism, the interface of immune and metabolic responses in health and disease, has emerged as a novel theme in studies of chronic inflammatory pathologies (Loftus and Finlay, 2016; Schertzer and Steinberg, 2014). Given mitochondria are at the core of metabolic adaptation to the changing environment, it is not surprising the close interaction between mitochondrial metabolism and immune signaling has been highlighted recently (Sancho et al., 2017). These mitochondrial components include electron transfer chain (ETC) system, tricarboxylic acid (TCA) cycle or fatty acid oxidation metabolic pathways, which influence innate and adaptive immune responses via various ways (Bohovych and Khalimonchuk, 2016). For example, metabolic intermediates such as acetyl coenzyme A (ac-CoA) can be used for DNA or protein modification which influence epigenetic regulation. Mitochondrial dysfunction perturbs alteration of adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ration, which, in turn, activates adenosine monophosphate-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis. Indeed, a highly ordered interactions between immune and metabolic responses have been demonstrated in multiple studies, identifying the complex immunometabolic signaling networks and the cellular and molecular events which underlie the development of chronic inflammatory diseases (Hotamisligil, 2017).

B. Pulmonary Disorders and Mitochondria

Many pulmonary disorders have recently been linked with mitochondrial dysfunction given the fact that many of these pulmonary disorders such as COPD and fibrosis are linked fundamentally with aberrant lung inflammatory and repair responses to external stimuli. The role of mitochondrial function has been an active area of investigation in pulmonary medicine. For example, COPD is a pulmonary disorder characterized by chronic inflammation and aberrant tissue remodeling in response to cigarette smoke exposure and other external stimuli. Studies have shown mitochondrial dysfunction in patients with COPD and have implicated several mitochondrial related genes such as MAVS and NLRX1 in its pathogenesis (Kang and Shadel, 2016; Kang et al., 2015; Yoon et al., 2016).

COPD is also characterized by exercise intolerance and skeletal muscle mitochondrial dysfunction, alteration of mitochondrial DNA content and reduced mitochondrial densities in these patients (Puente-Maestu et al., 2011; Puente-Maestu et al., 2009; Rabinovich et al., 2007). Mitochondrial fission as mediated by a specific cathepsin has been shown to be associated in lung models of lung tissue destruction as in emphysema (Zhang et al., 2014). Mitochondrial associated autophagy (or mitophagy) as well as iron-mediated mitochondria regulation have been shown to be important in COPD pathogenesis (Cloonan et al., 2016; Mizumura et al., 2014). Alveolar macrophages from COPD patients have impaired bacterial clearance due to failure to induce mitochondrial ROS in the macrophages in response to infection (Bewley et al., 2017).

Pulmonary fibrosis, a disease associated with aging, has been shown to have altered mitochondria (reviewed in (Mora et al., 2017)). Dysfunctional mitochondria in alveolar epithelial cells in IPF has been linked to reduced expression of PINK1 (a regulator of mitochondrial homeostasis) (Bueno et al., 2015; Patel et al., 2015). Other pulmonary disease such as asthma, cystic fibrosis and pulmonary hypertension have been reported to have mitochondrial dysfunction (Dromparis and Michelakis, 2013; Dromparis et al., 2013; Iyer et al., 2017; Valdivieso and Santa-Coloma, 2013).

C. Hepatic Disorders & Mitochondria

Mitochondrial dysfunction plays an important role in many liver diseases including drug-induced liver injury, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD) and others. Among these, NAFLD is the most common cause of chronic liver disease in adults, increasing in parallel with that of obesity and diabetes (Rinella, 2015). It encompasses diseases ranging from simple steatosis to non-alcoholic steatohepatitis (NSAH), fibrosis, and cirrhosis (Samuel and Shulman, 2017). Although the underlying pathophysiologic mechanism that contribute to the development and progression of NAFLD and NASH are complex (Samuel and Shulman, 2017), the activation of the innate immune system in association with chronic inflammation has been highlighted as an important feature of its pathogenesis (Arrese et al., 2016). Furthermore, maladaptation of mitochondrial oxidative flux has been indicated as a central feature of simple steatosis to NASH transition (Sunny et al., 2017). The liver is the hub of intermediary metabolism supporting key anabolic pathways and, in the setting of obesity and hepatic insulin resistance, continuous maladaptation of mitochondrial energetics, gene expression and morphology seems to play a key role in the pathogenesis (Koliaki et al., 2015).

D. Cancer-related inflammation & Mitochondria

Inflammation and dysregulated cellular energetics are important hallmarks of cancer. Many cancers arise from sites of infection, chronic irritation and inflammation. Cancers rely on many mitochondrial activities that include oxidative phosphorylation for cell growth and survival, suppression of mitochondria-mediated apoptosis and synthesis of nucleotide and amino acids. The host relies on the mitochondria protective responses to limit tumorigenesis. The tumor environment is an important contributor to the neoplastic process that can foster cell proliferation, survival and migration that is important for cancer development and progression with metastases (Shalapour and Karin, 2015). Tumor-associated inflammation can also result in immunosuppressive effects allowing for unchecked tumor growth but recent successful advances have taken advantage of using important immune checkpoint inhibitors in the treatment of many solid tumors (Nishino et al., 2017).

Somatic mutations in the mtDNA of human cancers are common events. It has been suggested that somatic mutations and decreased copy number of mtDNA in tumors cells can lead to mitochondrial dysfunction and cancer progression (Lee et al., 2005). However, how the specific mtDNA mutations regulate tumorigenesis is not clear. Mitochondrial enzyme defects, mtDNA mutations and or altered oncogenes/tumor suppressors in cancer result in mitochondrial dysfunctions and these dysfunctions are associated with deregulated cellular energetics as commonly seen in tumorigenesis (Petros et al., 2005; Shidara et al., 2005). Moreover, mitochondrial dysfunction promote cancer progression to cancer phenotypes that are apoptosis-resistant and or chemo-resistant with invasive properties (Higuchi et al., 2006; Ishikawa et al., 2008; Singh et al., 2009). More and more is being discovered how mitochondrial dysfunction influence inflammatory responses and cellular metabolisms, which are all important in all aspects of cancer biology.

E. Neuroinflammation & Mitochondrial dysfunction/DAMPs

Since the word ‘neuroinflammation’ was first coined in the 1980s to describe the accumulation of leukocytes in degenerating myelin and brain vessels in multiple sclerosis, the concept of ‘neuroinflammation’ has been extended to other neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and other neurological disorders (Masgrau et al., 2017; Ransohoff, 2016). Inflammation, which is characterized by the presence of immune and inflammatory cells, is indeed observed in these pathologies. Additional evidence of neuroinflammation can encompass the activation of inflammatory pathways, increased expression of cytokines or chemokines, and in some cases, disruption of the blood–brain barrier (BBB) accompanied by infiltration of peripheral immune cells (such as T cells) (Schwartz and Deczkowska, 2016). Because signs of neuroinflammation and neurodegeneration represent a ubiquitous pathological finding during the course of multiple neurodegenerative diseases, and, importantly, mitochondria may exert a crucial role in the pathogenesis of both inflammatory and neurodegenerative central nervous system disorders, there has been a consensus in which neuroinflammation and mitochondrial impairment may synergistically trigger a vicious cycle ultimately leading to neuronal death (Di Filippo et al., 2010; Wilkins et al., 2017; Witte et al., 2010). It is true, however, that the nature of neuroinflammation and the immunologic features of each neurodegenerative disorders are distinct and strikingly different among these conditions (Schwartz and Deczkowska, 2016). Furthermore, neuroinflammation has been difficult to define its pathogenic roles in relation to most neurodegenerative diseases (Ransohoff, 2016). Thus, it should be noted that the designations inflammation and neuroinflammation are not interchangeable and the term, ‘neuroinflammation,’ should be carefully and specifically applied (Filiou et al., 2014; Masgrau et al., 2017).

We apologize for the vast number of outstanding publications that could not be cited because of space limitations.

Funding Sources: This work was supported by NHLBI R01HL130283 (MJK), NIA R01AG053495 (MJK)) and NHLBI R01HL126094 (CDC).