Mitochondrial Dynamics in Pulmonary Hypertension

Abstract

Mitochondria are essential organelles for energy production, calcium homeostasis, redox signaling, and other cellular responses involved in pulmonary vascular biology and disease processes. Mitochondrial homeostasis depends on a balance in mitochondrial fusion and fission (dynamics). Mitochondrial dynamics are regulated by a viable circadian clock. Hypoxia and nicotine exposure can cause dysfunctions in mitochondrial dynamics, increases in mitochondrial reactive oxygen species generation and calcium concentration, and decreases in ATP production. These mitochondrial changes contribute significantly to pulmonary vascular oxidative stress, inflammatory responses, contractile dysfunction, pathologic remodeling, and eventually pulmonary hypertension. In this review article, therefore, we primarily summarize recent advances in basic, translational, and clinical studies of circadian roles in mitochondrial metabolism in the pulmonary vasculature. This knowledge may not only be crucial to fully understanding the development of pulmonary hypertension, but also greatly help to create new therapeutic strategies for treating this devastating disease and other related pulmonary disorders.

Keywords: circadian molecules; fission; fusion; hypoxia; mitochondria; nicotine; pulmonary vascular dysfunction.

Figure 1

Mitochondrial dynamics. Mitochondrial fusion begins with MFN1/2 in the outer membrane, and OPA1 in the inner membrane. MFN1/2 facilitates external membrane fixation and subsequent fusion. Mitochondrial fission begins after recruitment of DRP1 by MiD49/MiD51. DRP1 performs fission by self-polymerization around the mitochondrial outer membrane, where it contracts the organelle in a process that uses GTP hydrolysis. MFN1/2: Mitofusin 1 and 2; OPA-1: optic atrophy 1. DRP1: dynamin-related protein 1; MiD49: mitochondrial dynamics protein 49 kDA; MiD51: mitochondrial dynamics protein 51 kDA; Mff: mitochondrial fission factor; FIS1: fission protein 1.

Figure 2

Schematic of signaling pathways for nicotine/hypoxia-mediated cellular responses. Hypoxia or nicotine exposure can elevate RISP-mediated mitochondrial calcium concentration and ROS production leading to increased mitochondrial fission and mitophagy. These mitochondrial responses lead to the increase in [ROS]_i and [Ca²⁺]_i. The increased [ROS]_i and [Ca²⁺]_i cause pulmonary vasoconstriction and vascular remodeling, leading to pulmonary hypertension. These signaling pathways are also nicely regulated by the nuclear hormone receptor REV-ERBα- or REV-ERBβ-regulated transcription factor BMAL1- and CLOCK-controlled circadian access.