Mitochondria in lung biology and pathology: more than just a powerhouse

Abstract

An explosion of new information about mitochondria reveals that their importance extends well beyond their time-honored function as the "powerhouse of the cell." In this Perspectives article, we summarize new evidence showing that mitochondria are at the center of a reactive oxygen species (ROS)-dependent pathway governing the response to hypoxia and to mitochondrial quality control. The potential role of the mitochondrial genome as a sentinel molecule governing cytotoxic responses of lung cells to ROS stress also is highlighted. Additional attention is devoted to the fate of damaged mitochondrial DNA relative to its involvement as a damage-associated molecular pattern driving adverse lung and systemic cell responses in severe illness or trauma. Finally, emerging strategies for replenishing normal populations of mitochondria after damage, either through promotion of mitochondrial biogenesis or via mitochondrial transfer, are discussed.

Keywords: hypoxia; lung injury; mitochondrial biogenesis; mitochondrial transfer; mtDNA.

Fig. 1.

Conceptual model of oxygen sensing by mitochondria through the regulated generation of reactive oxygen species (ROS) that are released to the cytosol through the intermembrane space (IMS). IMS-PRDX5, peroxiredoxin-5 targeted to the IMS; PHD, hypoxia-inducible factor (HIF) prolyl hydroxylase; III, mitochondrial complex III.

Fig. 2.

Fate and biological actions of the oxidatively damaged mitochondrial genome that warrant characterization of mtDNA as a “sentinel molecule.” See text for details. DAMPs, damage associated molecular patterns; PTP, permeability transition pore.

Fig. 3.

Plasmacytoid dendritic cells (pDCs) play a central role in orchestrating both pro- and anti-inflammatory responses. A: during acute tissue injury mitochondrial DNA (mtDNA) and mitochondrial transcription factor A (TFAM) released from damaged cells and contaminating bacteria is sensed by pDCs to promote simultaneous release of TNF-α and IFN-α, which promotes the simultaneous activation of proinflammatory and regulatory immune cells. Thus pDCs are poised to orchestrate a localized and self-limited inflammatory response. Presumably, excessive pDCs activation (e.g., massive cell injury) could promote systemic pro- and anti-inflammatory immune responses. B: in splenocyte cultures representing complex immune cell interactions typically occurring in vivo release of IFN-α and TNF-α in response to immunogenic (CpGA) DNA is enhanced by TFAM and depletion of pDCs [by magnetic MicroBead selection (Miltenyi Biotec, Auburn, CA)], representing <3% of the total cell population from the splenocyte cultures, is shown to greatly suppress the immune response. Thus pDCs are important “amplifiers” of the immune response to TFAM and DNA. *P < 0.01, compared with corresponding CpGA DNA treatment alone; †P < 0.01, relative to matching treatment in the High pDC group; and ‡P < 0.01, compared with corresponding CpGA DNA treatment alone and the matching treatment in the high-pDC group. PMN, neutrophil; MΦ, macrophage; T-eff, effector CD4+ T cell; T-reg, regulatory T cell.

Fig. 4.

Integrated process of mitochondrial quality control in the maintenance of mitochondrial homeostasis. The diagram illustrates the simplified relationship between mitochondrial biogenesis and selective mitochondrial autophagy or mitophagy. The cycle is accelerated by oxidative stress and is monitored and regulated by redox sensors including the physiological gases.

Fig. 5.

Sequence of events leading to mitochondrial transfer from alveolus-attached bone-marrow-derived stromal cells (BMSCs) to the alveolar epithelium. The sketch of the distal airway (left) shows the arrival of airway instilled BMSCs (MSC) in alveoli composed of alveolar type 1 and type 2 cells (AT2 and AT2, respectively) and alveolar macrophages (AM). Subsequent processes in the alveolus (right) are 1) BMSCs adhere to the alveolar epithelium through Cx43 interactions; 2) gap junctions form between BMSCs and the epithelium; 3) calcium levels increase in the BMSCs; and 4) BMSCs release mitochondria-containing microvesicles which enter the epithelium and release their mitochondria in the cytosol.