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Mitochondria in the Pulmonary Vasculature in Health and Disease: Oxygen‐Sensing, Metabolism, and Dynamics

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Abstract

In lung vascular cells, mitochondria serve a canonical metabolic role, governing energy homeostasis. In addition, mitochondria exist in dynamic networks, which serve noncanonical functions, including regulation of redox signaling, cell cycle, apoptosis, and mitochondrial quality control. Mitochondria in pulmonary artery smooth muscle cells (PASMC) are oxygen sensors and initiate hypoxic pulmonary vasoconstriction. Acquired dysfunction of mitochondrial metabolism and dynamics contribute to a cancer‐like phenotype in pulmonary arterial hypertension (PAH). Acquired mitochondrial abnormalities, such as increased pyruvate dehydrogenase kinase (PDK) and pyruvate kinase muscle isoform 2 (PKM2) expression, which increase uncoupled glycolysis (the Warburg phenomenon), are implicated in PAH. Warburg metabolism sustains energy homeostasis by the inhibition of oxidative metabolism that reduces mitochondrial apoptosis, allowing unchecked cell accumulation. Warburg metabolism is initiated by the induction of a pseudohypoxic state, in which DNA methyltransferase (DNMT)‐mediated changes in redox signaling cause normoxic activation of HIF‐1α and increase PDK expression. Furthermore, mitochondrial division is coordinated with nuclear division through a process called mitotic fission. Increased mitotic fission in PAH, driven by increased fission and reduced fusion favors rapid cell cycle progression and apoptosis resistance. Downregulation of the mitochondrial calcium uniporter complex (MCUC) occurs in PAH and is one potential unifying mechanism linking Warburg metabolism and mitochondrial fission. Mitochondrial metabolic and dynamic disorders combine to promote the hyperproliferative, apoptosis‐resistant, phenotype in PAH PASMC, endothelial cells, and fibroblasts. Understanding the molecular mechanism regulating mitochondrial metabolism and dynamics has permitted identification of new biomarkers, nuclear and CT imaging modalities, and new therapeutic targets for PAH. © 2020 American Physiological Society. Compr Physiol 10:713‐765, 2020.

Figure 1. Figure 1. System for homeostatic oxygen‐sensing. This diagram indicates specialized tissues sensing local oxygen level. In response to hypoxia, the carotid body, located at the carotid‐artery bifurcation, increases action‐potential frequency in the carotid‐sinus nerve, thus stimulating respiration. The small resistance pulmonary and fetoplacental arteries exhibit hypoxic vasoconstriction, which optimizes oxygen transfer in the lung and placenta. On the contrary, the ductus arteriosus, contracts with increased oxygen tensions, redirecting blood through the newly expanded lungs of the newborn. The neuroepithelial bodies in the lungs and adrenomedullary cells in the fetus also sense oxygen. Adapted, with permission, from Weir EK, et al., 2005 333.
Figure 2. Figure 2. Ventilation/perfusion matching in vivo. A chest X‐ray of a patient with postoperative atelectasis of the right lower lobe. Hypoventilation is observed in the ventilation (V) study and localized hypoxic pulmonary vasoconstriction (HPV) elicits a corresponding reduction in perfusion (Q). Adapted, with permission, from Michelakis ED, et al., 2004 210.
Figure 3. Figure 3. (A) Schematic of RISP as the mitochondrial oxygen‐sensor. This schematic illustrates a proposed mechanism by which increased ROS production at RISP, a component of ETC Complex III in response to hypoxia stimulates HPV. This group finds that loss of RISP attenuates acute oxygen‐sensing. IMS, intermembrane space; KO, knockout; NAD+, nicotinamide adenine dinucleotide; NADH, NAD+ reduced; PASMC, pulmonary arterial smooth muscle cells; RISP, Rieske iron‐sulfur protein; ROS, reactive oxygen species; SASMC, systemic arterial smooth muscle cells; YC2.3‐FRET, the calcium‐sensitive, Förster resonance energy transfer sensor. Reprinted, with permission, from Waypa GB, et al., 2013 328. Copyright © 2019 American Thoracic Society. (B‐E) NADH dehydrogenase [ubiquinone] iron‐sulfur protein 2 (Ndufs2) is the pulmonary vascular oxygen sensor. This work shows the evidence that hypoxic inhibition of ETC complex I (and Ndufs2) reduces mitochondrial‐derived ROS production, triggering HPV. Schematic showing the pulmonary vasculature and PASMC mitochondria during normoxia (left) and hypoxia (right). (B) During normoxia, mitochondrial H2O2 production and elevated NAD/NADH ratio result in an oxidative environment and leads to oxidation of sulfhydryl groups (S‐S) on Kv channels, thereby increasing their open state probability, while the CaL channel remains closed. (C) Hypoxia lowers mitochondrial superoxide and hydrogen peroxide levels which, coupled with accumulation of NADH, result in depolarization of the cell, closing Kv channels and thereby increasing the opening of CaL channels and triggering HPV. (D) Intact Ndufs2 is required for optimal Complex I function, maintenance of circulating normoxic H2O2 levels and sensing of changes in O2. (E) Inhibition of Complex I, whether caused by hypoxic, pharmacological or molecular inhibition of Ndufs2 results in a more reduced SMC redox state, inhibiting Kv channel expression and a loss of activation of the CaL channel and vasoconstriction. Adapted, with permission, from Dunham‐Snary KJ, et al., 2019 86.
Figure 4. Figure 4. Contradictory roles for ROS in oxygen‐sensing and HPV. (A) Hypoxic pulmonary vasoconstriction (HPV) is a result of hypoxia‐induced decrease in reactive oxygen species (ROS) signaling. (B) HPV is a result of a paradoxical increase in ROS signaling. It is suspected the differences between these models reflect unstated and unrecognized differences in methodology (related to differences in pH, PO2, etc.), tissues studied (cultured cells vs. freshly isolated cells and PA rings), and temporal differences in the phase of HPV studied (<15 min versus later). cADPR, cyclic ADP‐ribose; [Ca2+]i, intracellular calcium concentration; CCE, capacitative calcium entry; ETC, electron transport chain; cGMP, cyclic guanosine monophosphate; GSH/GSSG, glutathione (reduced/oxidized); H2O2, hydrogen peroxide; Kv, voltage‐gated potassium channel; NADH/NAD+, nicotinamide adenine dinucleotide (reduced/oxidized); ROS, reactive oxygen species. Adapted, with permission, from Waypa GB and Schumacker PT, 2005 330.
Figure 5. Figure 5. Single‐lung anesthesia. (A) Bronchoscopy revealing endotracheal lesion; (B) a double‐lumen tube that permits single‐lung ventilation; (C) two‐lung ventilation during exposure of the operative field (top, red arrows highlight lack of oxygenation to a region of the lung), and collapse of the operative lung after inflation of the occluder (bottom, white arrows indicate reduction in blood flow to the collapsed lung) resulting in single‐lung ventilation/anesthesia. Adapted, with permission, from Nagendran J, et al., 2006 219.
Figure 6. Figure 6. Pulmonary vascular remodeling in pulmonary hypertension. Cross‐section of a normal pulmonary arteriole and a pulmonary arteriole with pulmonary hypertension. All three layers of the pulmonary vessel undergo remodeling in pulmonary hypertension, including proliferation of abnormal endothelial cells in the intima, hypertrophy, proliferation and distal migration of smooth muscle cells, proliferation of fibroblasts with increased extracellular matrix deposition, and increased recruitment of leukocytes in the adventitia.
Figure 7. Figure 7. Mitochondria exist in fragmented networks in PAH. Mitochondria from three adjacent PAH PASMC. The nuclei are not stained in this image and in aggregate the mitochondria in these three cells create the artistic impression of a dragon's head. The mitochondria are stained red with the potentiometric dye tetramethyl‐rhodamine (TMRM). Scale bar: 20 μm.
Figure 8. Figure 8. A simplified scheme of mitochondrial fission and fusion in mammalian cells. (A) Schematic representation of fusion. The outer membrane of two adjacent mitochondria is tethered by the interaction in trans of the HR2 domains of mitofusins (Mfns). GTP binding and hydrolysis cause conformational change of Mfns leading to outer mitochondrial membrane (OMM) fusion. Following OMM fusion, OPA1 drives the inner mitochondrial membrane (IMM) fusion. (B) Schematic representation of fission. Fission is initiated by endoplasmic reticulum (ER) mediated pre‐Drp1 constriction and marks the site for further constriction. Drp1 is recruited from the cytosol to the fission site via its receptors (Mff, MiD49, and MiD51) and forms contractile rings at the fission site. GTP hydrolysis leads to Drp1 conformational changes and constriction. Following this, Dnm2 is recruited to the constricted neck and further constriction (scission) occurs to complete fission. Then the fission machinery is disassembled by ubiquitination and proteasomal degradation (reviewed in Ref. 9).
Figure 9. Figure 9. Mitochondria are fragmented in PAH. Representative images of mitochondrial networks of normal PASMC and PAH PASMC stained with the potentiometric dye TMRM (red). Mitochondrial network appears more fragmented in PAH PASMC as compared to the mitochondria from normal PASMC. Adapted, with permission, from Chen KH, et al., 2018 59.
Figure 10. Figure 10. Schematic representations of the proposed role of epigenetically mediated upregulation of MiD49 and MiD51 in PAH. (A) Upregulation of MiDs on the outer mitochondrial membrane (OMM) increases mitochondrial fission and promotes cell proliferation in pulmonary arterial hypertension (PAH) pulmonary artery smooth muscle cells (PASMC). Downregulation of miR‐34a‐3p expression accounts for the increased MiD expression and contributes to the pathogenesis of PAH. (B) Silencing of MiD49 and MiD51, by siMiD49 and siMiD51, or by administering miR‐34a‐3p to PAH PASMC, promotes fusion and attenuates proliferation of PAH PASMC.
Figure 11. Figure 11. Silencing of MiD49 and MiD51 inhibits mitochondrial fission in PAH PASMC. (A) Mitochondrial fragmentation in PAH PASMC is reversed by silencing of MiD49 or MiD51. Representative images of mitochondrial networks of PAH PASMC. PAH PASMC were transfected with the specified siRNA, infected with Adv‐mNeon Green and imaged after 48 h following infection. Mitochondria were color coded by their morphology: red, punctate; green: intermediate; purple, filamentous. Scale bar: 10 μm. (B) Silencing of MiD49 or MiD51 inhibits mitochondrial fission. Mitochondrial fragmentation was quantified by mitochondrial fragmentation count (MFC) on the left and by a machine learning algorithm that quantified the percentage area of punctate, intermediate, and filamentous mitochondria of each image (on the right side of panel B). Adapted, with permission, from Chen KH, et al., 2018 59.
Figure 12. Figure 12. Schematic representation of the proposed mechanism for metabolic reprogramming in pulmonary hypertension fibroblast (PH‐Fibs). In PH‐Fibs, an alternative splicing complex containing PTBP1 (polypyrimidine tract binding protein 1), hnRNP (heterogeneous nuclear ribonucleoprotein) A1, and hnRNPA2 regulate the state of pyruvate kinase muscle (PKM) isoform expression. In the presence of PTBP, exon 10 is included in the mature PKM transcript, whereas exon 9 is excluded, resulting in an increased PKM2/PKM1 ratio which is an important mediator of aerobic glycolysis and increased proliferation. Expression of PTBP1 is modulated by its upstream regulator, microRNA‐124 (miRNA‐124). miR‐124 mimic, siPTBP1, TEPP‐46, shikonin (PKM2 inhibitors), and treatment with HDACi restores normal PKM2/PKM1 ratio and reverse Warburg effect in PH‐Fib. miR‐124‐PTBP1‐PKM axis is a potential therapeutic target for PH.
Figure 13. Figure 13. Role of hypoxia‐inducible factor‐1α (HIF‐1α) in the PASMC under normoxia, hypoxia, and pseudohypoxia (as occurs in PAH). (A) Under normoxic conditions, HIF‐1α is hydroxylated by prolyl hydroxylase domain proteins (PHD), using molecular oxygen, leading to interaction with Von Hipple‐Lindau (VHL) and degradation by ubiquitin‐proteasome pathway. (B) Under hypoxic condition, there is a decrease in mitochondrial H2O2 production and HIF‐1α expression is stabilized. HIF‐1α translocates to the nucleus where it dimerizes with HIF‐1β and recruits coactivators at the hypoxia response element (HRE) to modulate transcription of target genes. (C) In PAH PASMC low SOD2 expression, rather than environmental hypoxia, decreases H2O2 production, creating a pseudohypoxic state, thereby activating HIF‐1α. HIF‐1α, in turn, activates PDK transcription resulting in the inhibition of PDH and further reduction in ROS production. Decreased ROS inhibits certain oxygen‐ and redox‐sensitive potassium channels, including Kv1.5, resulting in PASMC depolarization and calcium overload.
Figure 14. Figure 14. Visualization of mitochondrial DNA replication machinery. Confocal microscopy of a normal human pulmonary artery smooth muscle cell (PASMC) with immunofluorescent labeling of nuclear DNA (blue), mitochondria (red) and transcription factor A mitochondrial (TFAM, green). TFAM is a nuclear‐encoded, DNA binding protein that activates transcription of mtDNA; mtDNA replication precedes mitochondrial biogenesis. Scale bar: 5 μm.
Figure 15. Figure 15. Increased level of miR‐25 and miR‐138 in PAH‐PASMC directly inhibit the expression of mitochondrial calcium uniporter (MCU). The loss of MCU expression, exacerbated by increased expression of mitochondrial calcium uptake protein 1 (MCU1), reduces the function of the MCU complex. This simultaneously overloads the cytosolic calcium pool while depriving the mitochondria of calcium. The former triggers PASMC migration and proliferation (and vasoconstriction), whereas the latter affects mitochondrial metabolism, inhibiting pyruvate dehydrogenase and promoting a shift to uncoupled glycolysis (the Warburg phenomenon). In aggregate, these epigenetic changes promote cell proliferation and apoptosis resistance. IP3, inositol 1,4,5‐trisphosphate receptor; VDAC, voltage‐dependent anion channel. Adapted, with permission, from Hong Z, et al., 2017 141.
Figure 16. Figure 16. Time course of metabolic changes on  18FDG PET scans of the lung in rats with MCT‐PAH. (A) Pulmonary arterial acceleration time (PAAT) was measured by pulsed‐wave Doppler echocardiography. Measurements were made before MCT injection and weekly thereafter. The arrow at the 3‐week time point indicates systolic notching of the pulmonary artery Doppler envelope, typical of severe PH. (B) PAAT is inversely related to the mean pulmonary artery pressure and decreases during the development of pulmonary hypertension. Starting from week 2, a significant reduction in PAAT is observed. (C) Representative positron emission tomography (PET) scans. Note the increased 18F‐fluorodeoxyglucose (FDG) uptake in the right ventricle (RV) and the lung parenchyma of MCT animals. LV, left ventricle. (D) Quantification of pulmonary 18FDG uptake measured with PET. Starting from week 2, significantly higher lung FDG uptake was observed. (E) Correlation analysis demonstrates the inverse relationship between PAAT and 18FDG uptake. Seven rats were imaged at each time point. Adapted, with permission, from Marsboom G, et al., 2012 193.
Figure 17. Figure 17. Myocardial perfusion imaging (MPI)‐PET (upper panel), FDG‐PET (middle panel), and FTHA‐PET images (lower panel) in three patients with PAH of mild, moderate, or severe degree. The patients' RVEF and mPAP are reported below the images. Note the progressive increase in RV uptake relative to the LV with worsening PAH. Also note that the RV FDG uptake relative to the LV is similar to the RV/LV perfusion tracer uptake in the patients with mild and moderate PAH (left and center panels), but RV/LV FDG uptake is increased relative to perfusion in the patient with severe PAH (right panel). Thus there is a perfusion/metabolism mismatch in the RV in these patients and suggests that there is RV myocardial ischemia or hibernation. RVEF, right ventricular ejection fraction; mPAP, mean pulmonary arterial pressure; RV, right ventricle; LV, left ventricle; PAH, pulmonary arterial hypertension; FDG, 18F‐fluoro‐2‐deoxyglucose; FTHA, 18F‐fluoro‐6‐thioheptadecanoic acid. Adapted, with permission, from Ohira H, et al., 2016 225.
Figure 18. Figure 18. Consequences of pulmonary hypertension include obstructive pulmonary vascular remodeling and right ventricular hypertrophy and dilatation. Adapted, with permission, from Ho SY and Nihoyannopoulos P, 2006 138 and Ryan JJ, et al., 2015 272.
Figure 19. Figure 19. Active and completed clinical trials returned using search term “pulmonary hypertension” and filter “metabolism OR mitochondria.”
Figure 20. Figure 20. Mechanism of right ventricular ischemia in pulmonary hypertension. Right ventricular dysfunction causes an increase in right ventricular systolic pressure (RVSP) and right ventricular end‐diastolic pressure (RVEDP) which, in turn, compresses the left ventricle (LV) leading to the decrease in LV filling, cardiac output, and aortic pressure. Decreased aortic pressure and increased RVEDP contribute to decrease in subendocardial blood flow and increase in myocardial oxygen uptake respectively. This finally results in myocardial ischemia. Adapted, with permission, from Crystal GJ and Pagel PS, 2018 77.
Figure 21. Figure 21. The Randle cycle in the hypertrophied right ventricular cardiomyocyte. The partial inhibition of fatty acid oxidation (FAO), by trimetazidine (TMZ) or ranolazine (RAN), increases pyruvate dehydrogenase (PDH) activity and improves glucose oxidation (GO). The reciprocal relationship between FAO and GO is known as the Randle's cycle. Adapted, with permission, from Fang YH, et al., 2012 96.
Figure 22. Figure 22. Dichloroacetate promotes glucose oxidation by inhibiting the pyruvate dehydrogenase kinase (PDK) in right ventricular hypertrophy caused by pulmonary hypertension. In right ventricular hypertrophy (RVH), activation of various transcription factors, including FOXO1, cMyc, and HIF‐1α upregulates expression of many glycolytic genes including pyruvate dehydrogenase kinase (PDK) which is the inhibitor of pyruvate dehydrogenase (PDH) and suppresses mitochondrial respiration. Dichloroacetate (DCA) suppresses glycolysis by inhibiting PDK thereby promoting glucose oxidation. ETC, electron transport chain; HK, hexokinase; H2O2, hydrogen peroxide; LDHA, lactate dehydrogenase A; PFK, phosphofructokinase. Adapted, with permission, from Ryan JJ and Archer SL, 2014 270.
Figure 23. Figure 23. The role of inositol‐requiring protein 1α (IRE1α)–X‐box‐binding protein 1 (XBP1s) pathway in heart failure with preserved ejection fraction (HFpEF). High‐fat diet (metabolic stress) and hypertension induced by Nw‐nitro‐l‐arginine methyl ester (l‐NAME) (mechanical stress) induce symptoms of HFpEF, including impaired filling of left ventricle, reduced exercise capacity, lung congestion, and increased systemic inflammation. Schiattarella et al. noted increased expression of inducible nitric oxide synthase (iNOS), which led to marked overproduction of nitric oxide (NO). Increased NO binds to sulfur atoms of IRE1a, and S‐nitrosylation decreases IRE1a activity. IRE1a is an important component of the unfolded protein response (UPR), which protects cells from misfolded proteins. Decreased IRE1a activity results in reduced splicing of XBP1s messenger RNA. XBP1s is a transcription factor that activates UPR genes, and the disruption of the UPR is postulated to eventually result in HFpEF. Figure adopted from Amgalan and Kitsis with permission. Adapted, with permission, from Amgalan D and Kitsis RN, 2019 7.
Figure 24. Figure 24. Schematic diagram of molecular pathways involved in the pathogenesis of PAH. Upstream regulators of mitochondrial mediators, such as microRNA, transcription factors, contribute to the dysregulation of mitochondrial mediator proteins, causing excessive mitochondrial fission/reduced mitochondrial fusion, aerobic glycolysis, increased proliferation decreased apoptosis, and decreased mitochondrial biogenesis.


Figure 1. System for homeostatic oxygen‐sensing. This diagram indicates specialized tissues sensing local oxygen level. In response to hypoxia, the carotid body, located at the carotid‐artery bifurcation, increases action‐potential frequency in the carotid‐sinus nerve, thus stimulating respiration. The small resistance pulmonary and fetoplacental arteries exhibit hypoxic vasoconstriction, which optimizes oxygen transfer in the lung and placenta. On the contrary, the ductus arteriosus, contracts with increased oxygen tensions, redirecting blood through the newly expanded lungs of the newborn. The neuroepithelial bodies in the lungs and adrenomedullary cells in the fetus also sense oxygen. Adapted, with permission, from Weir EK, et al., 2005 333.


Figure 2. Ventilation/perfusion matching in vivo. A chest X‐ray of a patient with postoperative atelectasis of the right lower lobe. Hypoventilation is observed in the ventilation (V) study and localized hypoxic pulmonary vasoconstriction (HPV) elicits a corresponding reduction in perfusion (Q). Adapted, with permission, from Michelakis ED, et al., 2004 210.


Figure 3. (A) Schematic of RISP as the mitochondrial oxygen‐sensor. This schematic illustrates a proposed mechanism by which increased ROS production at RISP, a component of ETC Complex III in response to hypoxia stimulates HPV. This group finds that loss of RISP attenuates acute oxygen‐sensing. IMS, intermembrane space; KO, knockout; NAD+, nicotinamide adenine dinucleotide; NADH, NAD+ reduced; PASMC, pulmonary arterial smooth muscle cells; RISP, Rieske iron‐sulfur protein; ROS, reactive oxygen species; SASMC, systemic arterial smooth muscle cells; YC2.3‐FRET, the calcium‐sensitive, Förster resonance energy transfer sensor. Reprinted, with permission, from Waypa GB, et al., 2013 328. Copyright © 2019 American Thoracic Society. (B‐E) NADH dehydrogenase [ubiquinone] iron‐sulfur protein 2 (Ndufs2) is the pulmonary vascular oxygen sensor. This work shows the evidence that hypoxic inhibition of ETC complex I (and Ndufs2) reduces mitochondrial‐derived ROS production, triggering HPV. Schematic showing the pulmonary vasculature and PASMC mitochondria during normoxia (left) and hypoxia (right). (B) During normoxia, mitochondrial H2O2 production and elevated NAD/NADH ratio result in an oxidative environment and leads to oxidation of sulfhydryl groups (S‐S) on Kv channels, thereby increasing their open state probability, while the CaL channel remains closed. (C) Hypoxia lowers mitochondrial superoxide and hydrogen peroxide levels which, coupled with accumulation of NADH, result in depolarization of the cell, closing Kv channels and thereby increasing the opening of CaL channels and triggering HPV. (D) Intact Ndufs2 is required for optimal Complex I function, maintenance of circulating normoxic H2O2 levels and sensing of changes in O2. (E) Inhibition of Complex I, whether caused by hypoxic, pharmacological or molecular inhibition of Ndufs2 results in a more reduced SMC redox state, inhibiting Kv channel expression and a loss of activation of the CaL channel and vasoconstriction. Adapted, with permission, from Dunham‐Snary KJ, et al., 2019 86.


Figure 4. Contradictory roles for ROS in oxygen‐sensing and HPV. (A) Hypoxic pulmonary vasoconstriction (HPV) is a result of hypoxia‐induced decrease in reactive oxygen species (ROS) signaling. (B) HPV is a result of a paradoxical increase in ROS signaling. It is suspected the differences between these models reflect unstated and unrecognized differences in methodology (related to differences in pH, PO2, etc.), tissues studied (cultured cells vs. freshly isolated cells and PA rings), and temporal differences in the phase of HPV studied (<15 min versus later). cADPR, cyclic ADP‐ribose; [Ca2+]i, intracellular calcium concentration; CCE, capacitative calcium entry; ETC, electron transport chain; cGMP, cyclic guanosine monophosphate; GSH/GSSG, glutathione (reduced/oxidized); H2O2, hydrogen peroxide; Kv, voltage‐gated potassium channel; NADH/NAD+, nicotinamide adenine dinucleotide (reduced/oxidized); ROS, reactive oxygen species. Adapted, with permission, from Waypa GB and Schumacker PT, 2005 330.


Figure 5. Single‐lung anesthesia. (A) Bronchoscopy revealing endotracheal lesion; (B) a double‐lumen tube that permits single‐lung ventilation; (C) two‐lung ventilation during exposure of the operative field (top, red arrows highlight lack of oxygenation to a region of the lung), and collapse of the operative lung after inflation of the occluder (bottom, white arrows indicate reduction in blood flow to the collapsed lung) resulting in single‐lung ventilation/anesthesia. Adapted, with permission, from Nagendran J, et al., 2006 219.


Figure 6. Pulmonary vascular remodeling in pulmonary hypertension. Cross‐section of a normal pulmonary arteriole and a pulmonary arteriole with pulmonary hypertension. All three layers of the pulmonary vessel undergo remodeling in pulmonary hypertension, including proliferation of abnormal endothelial cells in the intima, hypertrophy, proliferation and distal migration of smooth muscle cells, proliferation of fibroblasts with increased extracellular matrix deposition, and increased recruitment of leukocytes in the adventitia.


Figure 7. Mitochondria exist in fragmented networks in PAH. Mitochondria from three adjacent PAH PASMC. The nuclei are not stained in this image and in aggregate the mitochondria in these three cells create the artistic impression of a dragon's head. The mitochondria are stained red with the potentiometric dye tetramethyl‐rhodamine (TMRM). Scale bar: 20 μm.


Figure 8. A simplified scheme of mitochondrial fission and fusion in mammalian cells. (A) Schematic representation of fusion. The outer membrane of two adjacent mitochondria is tethered by the interaction in trans of the HR2 domains of mitofusins (Mfns). GTP binding and hydrolysis cause conformational change of Mfns leading to outer mitochondrial membrane (OMM) fusion. Following OMM fusion, OPA1 drives the inner mitochondrial membrane (IMM) fusion. (B) Schematic representation of fission. Fission is initiated by endoplasmic reticulum (ER) mediated pre‐Drp1 constriction and marks the site for further constriction. Drp1 is recruited from the cytosol to the fission site via its receptors (Mff, MiD49, and MiD51) and forms contractile rings at the fission site. GTP hydrolysis leads to Drp1 conformational changes and constriction. Following this, Dnm2 is recruited to the constricted neck and further constriction (scission) occurs to complete fission. Then the fission machinery is disassembled by ubiquitination and proteasomal degradation (reviewed in Ref. 9).


Figure 9. Mitochondria are fragmented in PAH. Representative images of mitochondrial networks of normal PASMC and PAH PASMC stained with the potentiometric dye TMRM (red). Mitochondrial network appears more fragmented in PAH PASMC as compared to the mitochondria from normal PASMC. Adapted, with permission, from Chen KH, et al., 2018 59.


Figure 10. Schematic representations of the proposed role of epigenetically mediated upregulation of MiD49 and MiD51 in PAH. (A) Upregulation of MiDs on the outer mitochondrial membrane (OMM) increases mitochondrial fission and promotes cell proliferation in pulmonary arterial hypertension (PAH) pulmonary artery smooth muscle cells (PASMC). Downregulation of miR‐34a‐3p expression accounts for the increased MiD expression and contributes to the pathogenesis of PAH. (B) Silencing of MiD49 and MiD51, by siMiD49 and siMiD51, or by administering miR‐34a‐3p to PAH PASMC, promotes fusion and attenuates proliferation of PAH PASMC.


Figure 11. Silencing of MiD49 and MiD51 inhibits mitochondrial fission in PAH PASMC. (A) Mitochondrial fragmentation in PAH PASMC is reversed by silencing of MiD49 or MiD51. Representative images of mitochondrial networks of PAH PASMC. PAH PASMC were transfected with the specified siRNA, infected with Adv‐mNeon Green and imaged after 48 h following infection. Mitochondria were color coded by their morphology: red, punctate; green: intermediate; purple, filamentous. Scale bar: 10 μm. (B) Silencing of MiD49 or MiD51 inhibits mitochondrial fission. Mitochondrial fragmentation was quantified by mitochondrial fragmentation count (MFC) on the left and by a machine learning algorithm that quantified the percentage area of punctate, intermediate, and filamentous mitochondria of each image (on the right side of panel B). Adapted, with permission, from Chen KH, et al., 2018 59.


Figure 12. Schematic representation of the proposed mechanism for metabolic reprogramming in pulmonary hypertension fibroblast (PH‐Fibs). In PH‐Fibs, an alternative splicing complex containing PTBP1 (polypyrimidine tract binding protein 1), hnRNP (heterogeneous nuclear ribonucleoprotein) A1, and hnRNPA2 regulate the state of pyruvate kinase muscle (PKM) isoform expression. In the presence of PTBP, exon 10 is included in the mature PKM transcript, whereas exon 9 is excluded, resulting in an increased PKM2/PKM1 ratio which is an important mediator of aerobic glycolysis and increased proliferation. Expression of PTBP1 is modulated by its upstream regulator, microRNA‐124 (miRNA‐124). miR‐124 mimic, siPTBP1, TEPP‐46, shikonin (PKM2 inhibitors), and treatment with HDACi restores normal PKM2/PKM1 ratio and reverse Warburg effect in PH‐Fib. miR‐124‐PTBP1‐PKM axis is a potential therapeutic target for PH.


Figure 13. Role of hypoxia‐inducible factor‐1α (HIF‐1α) in the PASMC under normoxia, hypoxia, and pseudohypoxia (as occurs in PAH). (A) Under normoxic conditions, HIF‐1α is hydroxylated by prolyl hydroxylase domain proteins (PHD), using molecular oxygen, leading to interaction with Von Hipple‐Lindau (VHL) and degradation by ubiquitin‐proteasome pathway. (B) Under hypoxic condition, there is a decrease in mitochondrial H2O2 production and HIF‐1α expression is stabilized. HIF‐1α translocates to the nucleus where it dimerizes with HIF‐1β and recruits coactivators at the hypoxia response element (HRE) to modulate transcription of target genes. (C) In PAH PASMC low SOD2 expression, rather than environmental hypoxia, decreases H2O2 production, creating a pseudohypoxic state, thereby activating HIF‐1α. HIF‐1α, in turn, activates PDK transcription resulting in the inhibition of PDH and further reduction in ROS production. Decreased ROS inhibits certain oxygen‐ and redox‐sensitive potassium channels, including Kv1.5, resulting in PASMC depolarization and calcium overload.


Figure 14. Visualization of mitochondrial DNA replication machinery. Confocal microscopy of a normal human pulmonary artery smooth muscle cell (PASMC) with immunofluorescent labeling of nuclear DNA (blue), mitochondria (red) and transcription factor A mitochondrial (TFAM, green). TFAM is a nuclear‐encoded, DNA binding protein that activates transcription of mtDNA; mtDNA replication precedes mitochondrial biogenesis. Scale bar: 5 μm.


Figure 15. Increased level of miR‐25 and miR‐138 in PAH‐PASMC directly inhibit the expression of mitochondrial calcium uniporter (MCU). The loss of MCU expression, exacerbated by increased expression of mitochondrial calcium uptake protein 1 (MCU1), reduces the function of the MCU complex. This simultaneously overloads the cytosolic calcium pool while depriving the mitochondria of calcium. The former triggers PASMC migration and proliferation (and vasoconstriction), whereas the latter affects mitochondrial metabolism, inhibiting pyruvate dehydrogenase and promoting a shift to uncoupled glycolysis (the Warburg phenomenon). In aggregate, these epigenetic changes promote cell proliferation and apoptosis resistance. IP3, inositol 1,4,5‐trisphosphate receptor; VDAC, voltage‐dependent anion channel. Adapted, with permission, from Hong Z, et al., 2017 141.


Figure 16. Time course of metabolic changes on  18FDG PET scans of the lung in rats with MCT‐PAH. (A) Pulmonary arterial acceleration time (PAAT) was measured by pulsed‐wave Doppler echocardiography. Measurements were made before MCT injection and weekly thereafter. The arrow at the 3‐week time point indicates systolic notching of the pulmonary artery Doppler envelope, typical of severe PH. (B) PAAT is inversely related to the mean pulmonary artery pressure and decreases during the development of pulmonary hypertension. Starting from week 2, a significant reduction in PAAT is observed. (C) Representative positron emission tomography (PET) scans. Note the increased 18F‐fluorodeoxyglucose (FDG) uptake in the right ventricle (RV) and the lung parenchyma of MCT animals. LV, left ventricle. (D) Quantification of pulmonary 18FDG uptake measured with PET. Starting from week 2, significantly higher lung FDG uptake was observed. (E) Correlation analysis demonstrates the inverse relationship between PAAT and 18FDG uptake. Seven rats were imaged at each time point. Adapted, with permission, from Marsboom G, et al., 2012 193.


Figure 17. Myocardial perfusion imaging (MPI)‐PET (upper panel), FDG‐PET (middle panel), and FTHA‐PET images (lower panel) in three patients with PAH of mild, moderate, or severe degree. The patients' RVEF and mPAP are reported below the images. Note the progressive increase in RV uptake relative to the LV with worsening PAH. Also note that the RV FDG uptake relative to the LV is similar to the RV/LV perfusion tracer uptake in the patients with mild and moderate PAH (left and center panels), but RV/LV FDG uptake is increased relative to perfusion in the patient with severe PAH (right panel). Thus there is a perfusion/metabolism mismatch in the RV in these patients and suggests that there is RV myocardial ischemia or hibernation. RVEF, right ventricular ejection fraction; mPAP, mean pulmonary arterial pressure; RV, right ventricle; LV, left ventricle; PAH, pulmonary arterial hypertension; FDG, 18F‐fluoro‐2‐deoxyglucose; FTHA, 18F‐fluoro‐6‐thioheptadecanoic acid. Adapted, with permission, from Ohira H, et al., 2016 225.


Figure 18. Consequences of pulmonary hypertension include obstructive pulmonary vascular remodeling and right ventricular hypertrophy and dilatation. Adapted, with permission, from Ho SY and Nihoyannopoulos P, 2006 138 and Ryan JJ, et al., 2015 272.


Figure 19. Active and completed clinical trials returned using search term “pulmonary hypertension” and filter “metabolism OR mitochondria.”


Figure 20. Mechanism of right ventricular ischemia in pulmonary hypertension. Right ventricular dysfunction causes an increase in right ventricular systolic pressure (RVSP) and right ventricular end‐diastolic pressure (RVEDP) which, in turn, compresses the left ventricle (LV) leading to the decrease in LV filling, cardiac output, and aortic pressure. Decreased aortic pressure and increased RVEDP contribute to decrease in subendocardial blood flow and increase in myocardial oxygen uptake respectively. This finally results in myocardial ischemia. Adapted, with permission, from Crystal GJ and Pagel PS, 2018 77.


Figure 21. The Randle cycle in the hypertrophied right ventricular cardiomyocyte. The partial inhibition of fatty acid oxidation (FAO), by trimetazidine (TMZ) or ranolazine (RAN), increases pyruvate dehydrogenase (PDH) activity and improves glucose oxidation (GO). The reciprocal relationship between FAO and GO is known as the Randle's cycle. Adapted, with permission, from Fang YH, et al., 2012 96.


Figure 22. Dichloroacetate promotes glucose oxidation by inhibiting the pyruvate dehydrogenase kinase (PDK) in right ventricular hypertrophy caused by pulmonary hypertension. In right ventricular hypertrophy (RVH), activation of various transcription factors, including FOXO1, cMyc, and HIF‐1α upregulates expression of many glycolytic genes including pyruvate dehydrogenase kinase (PDK) which is the inhibitor of pyruvate dehydrogenase (PDH) and suppresses mitochondrial respiration. Dichloroacetate (DCA) suppresses glycolysis by inhibiting PDK thereby promoting glucose oxidation. ETC, electron transport chain; HK, hexokinase; H2O2, hydrogen peroxide; LDHA, lactate dehydrogenase A; PFK, phosphofructokinase. Adapted, with permission, from Ryan JJ and Archer SL, 2014 270.


Figure 23. The role of inositol‐requiring protein 1α (IRE1α)–X‐box‐binding protein 1 (XBP1s) pathway in heart failure with preserved ejection fraction (HFpEF). High‐fat diet (metabolic stress) and hypertension induced by Nw‐nitro‐l‐arginine methyl ester (l‐NAME) (mechanical stress) induce symptoms of HFpEF, including impaired filling of left ventricle, reduced exercise capacity, lung congestion, and increased systemic inflammation. Schiattarella et al. noted increased expression of inducible nitric oxide synthase (iNOS), which led to marked overproduction of nitric oxide (NO). Increased NO binds to sulfur atoms of IRE1a, and S‐nitrosylation decreases IRE1a activity. IRE1a is an important component of the unfolded protein response (UPR), which protects cells from misfolded proteins. Decreased IRE1a activity results in reduced splicing of XBP1s messenger RNA. XBP1s is a transcription factor that activates UPR genes, and the disruption of the UPR is postulated to eventually result in HFpEF. Figure adopted from Amgalan and Kitsis with permission. Adapted, with permission, from Amgalan D and Kitsis RN, 2019 7.


Figure 24. Schematic diagram of molecular pathways involved in the pathogenesis of PAH. Upstream regulators of mitochondrial mediators, such as microRNA, transcription factors, contribute to the dysregulation of mitochondrial mediator proteins, causing excessive mitochondrial fission/reduced mitochondrial fusion, aerobic glycolysis, increased proliferation decreased apoptosis, and decreased mitochondrial biogenesis.
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Teaching Material

Asish Dasgupta, Danchen Wu, Lian Tian, Ping Yu Xiong, Kimberly J. Dunham-Snary, Kuang-Hueih Chen, Elahe Alizadeh, Mehras Motamed, François Potus, Charles C.T. Hindmarch and Stephen L. Archer. Mitochondria in the Pulmonary Vasculature in Health and Disease: Oxygen-sensing, Metabolism, and Dynamics. Compr Physiol 10 : 2020, 713-765

Didactic Synopsis

Major Teaching Points:

1. Mitochondria in resistance pulmonary artery smooth muscle cells (PASMC) are oxygen sensors that transduce alveolar O2 to a diffusible redox signal that regulates ion channels and enzymes, leading to hypoxic pulmonary vasoconstriction.

2. Acquired abnormalities of mitochondrial metabolism and dynamics promotes a cancer like hyperproliferative, apoptosis-resistant, phenotype in all PAH vascular cells .

3. In PAH, acquired metabolic abnormalities include an increase in uncoupled aerobic glycolysis (Warburg metabolism) similar to that seen in cancer.

4. In PAH, Warburg metabolism is partially mediated by upregulation of PDK and an increased PKM2/PKM1 ratio.

5. Mitochondrial fragmentation, a hallmark of PAH, reflects an increased fission/fusion ratio caused by activation of Drp1, upregulation of MiD49 and MiD51, and downregulation of Mfn2.

6. Newly recognized mitochondrial pathways offer potential therapeutic targets for pulmonary vascular diseases, including: PDK inhibitors, PKM2 inhibitors, miR mimics and anti-miRs, inhibitors of Drp1 and its binding partners, and Mfn2 augmentation.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1:

Teaching points: This figure illustrates that homeostatic Oxygen Sensing System (HOSS) is a network of specialized tissues that sense O2 in their local environments and regulate vascular tone, ventilation or catecholamine secretion to optimize systemic oxygen delivery. The HOSS is made up of: type 1 cells in the carotid body, PASMC, fetoplacental arteries in the placenta, the ductus arteriosus (DA), adrenomedullary chromaffin cells of the adrenal glands, and neuroepithelial bodies, a type of neuroendocrine cell in the airways.

Figure 3A:

Teaching Points: This figure illustrates a hypothesis of oxygen sensing that involves increased ROS production under hypoxia. According to this hypothesis, the Rieske iron-sulfur subunit (RISP) of Complex III is the oxygen-sensor. Furthermore, hypoxia increases ROS and reflects auto-oxidation of the ETC, due to inhibition of the distal ETC. It is the rise in ROS in this model that is proposed to cause HPV.

Figure 3B-E:

Teaching Points: This figure illustrates an earlier and opposing hypothesis of oxygen sensing (compared to Figure 3). In this redox model there is decreased mitochondrial ROS production under hypoxia. NADH dehydrogenase [ubiquinone] iron-sulfur protein 2 (Ndufs2), the quinone binding site in ETC Complex I (and interestingly, not the RISP) has been characterized as the mitochondrial oxygen sensor in both the carotid body and the PASMC. Ndufs2 is the course of mitochondrial ROS and is inhibited by physiologic hypoxia. Inhibition of Ndufs2decreases mitochondrial H2O2 and activates the downstream vasoconstrictor mechanism of HPV. Normal function of Ndufs2 is required for hypoxia-induced increases in cytosolic calcium. Nebulized Ndufs2 reduces expression of Ndufs2 in vivo and inhibits HPV.

Figure 6:

Teaching Points: This figure illustrates the main pathological change of pulmonary vasculature, particularly in small, intrapulmonary arteries and arterioles in PAH. All layers of the pulmonary vessel wall (intima, media, adventitia) are involved in adverse vascular remodelling in PAH. Pathologic changes include intimal hyperplasia, medial hypertrophy, adventitial fibrosis and infiltration of inflammatory cells and progenitor cells.

Figure 8:

Teaching Points: This figure is a simplified schematic representation of mitochondrial fusion and fission. A) The major mediator of mitochondrial fission is dynamin related protein 1 (Drp1), while fusion is mediated by GTPases mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and optic atrophy 1 (OPA1). During fusion, the outer membrane of two adjacent mitochondria are tethered by the interaction in trans of the HR2 domains of Mfns. This is followed by GTP binding and hydrolysis contributing to the conformational change of Mfn2 which leads to the fusion of OMM. OMM fusion is followed by IMM fusion which is mediated by OPA1. B) During fission, ER-mediated pre-Drp1 constriction marks the site for further constriction. Drp1 is recruited to the mitochondria by its receptors (Mff, MiD49 and MiD51). On the OMM, Drp1 multimerizes forming a contractile ring at the fission site which is followed by GTP hydrolysis leading to constriction by the conformational changes of Drp1. This is followed by the recruitment of Dnm2 to the constriction site and further constriction (scission) occurs to complete fission. Then the fission machinery is disassembled.

Figure 9:

Teaching Points: This figure shows increased mitochondrial fragmentation due to elevated mitochondrial fission in PAH PASMC as compared to normal PASMC. This increase in mitochondrial fission in PAH PASMC is due in part to the increased expression and/or activity of Drp1 and its binding partners, MiD49 and MiD51.

Figure 10:

Teaching Points: This figure represents the role of Drp1 receptors MiD49 and MiD51 in pathogenesis of PAH. In PAH both MiDs are epigenetically upregulated by a decrease in miR-34a-3p expression. This increases mitochondrial fission and promotes cell proliferation in PAH PASMC. Silencing of MiD49 and MiD51, by siMiD49 and siMiD51, or by administering miR-34a-3p to PAH PASMC promotes fusion and attenuates proliferation of PAH PASMC.

Figure 12:

Teaching Points: This figure illustrates the dysregulation of miR-124/PTBP1/PKM pathway in PAH and its targeted treatments. Decreased expression of miR-124 increases the expression of its target, the splicing factor polypyrimidine-tract-binding protein (PTBP1), resulting in increased PKM2 expression, which enhances uncoupled aerobic glycolysis and increased lactate production while also decreasing translocation of pyruvate to mitochondria. Therefore, miR-124, siPTBP1, or HDACs may be therapeutic agents targeting the miR-124/PTBP1/PKM pathway in PAH.

Figure 13:

Teaching Points:

This figure illustrates the regulation of HIF-1α in normal and pathological conditions (PAH). Under normoxia, the prolyl hydroxylase domain proteins (PHD) and factor inhibiting HIF-1α (FIH-1) hydroxylates HIF-1α using molecular oxygen. Hydroxylated HIF-1α then interacts with Von Hipple-Lindau (VHL) and subsequently degraded by the ubiquitin proteasome pathway. Under hypoxic condition HIF-1α expression is stabilized and translocates to the nucleus. In the nucleus, it dimerizes with HIF-1β and recruits co-activators at the hypoxia response element (HRE) to initiate transcription of target genes. In PAH, low SOD2 results in decreased H2O2 creating a pseudohypoxic state activating HIF-1α. This in turn activates PDK resulting in the inhibition of PDH and reduced ROS production. Decreased ROS downregulates Kv1.5 resulting in depolarization and calcium overload.

Figure 15:

Teaching Points:

This figure illustrates the mechanism of downregulation of MCU in PAH PASMC. Decreased expression of MCU in PAH contributes to increased cytosolic calcium concentration and decreased mitochondrial calcium, which promotes cell proliferation and resistance to apoptosis in PAH PASMC. In PAH two of the upstream regulators of MCU expression are increased, namely miR-25 and miR-138.

Figure 16:

Teaching Points:

This figure illustrates a correlation between echocardiography change and glucose uptake in the development of MCT-PAH. The shortening of PAAT is dynamically correlated with increased uptake of FDG in the RV as shown by the PET/CT scanning.

Figure 17:

Teaching Points: This figure indicates a visual assessment to determine the role of RV ischemia and hibernation in patient with different PAH severity. Myocardial perfusion imaging (MPI)-PET (upper panel), 18F-fluoro-2-deoxyglucose (FDG)-PET (middle panel), and 18F-fluoro-6-thioheptadecanoic acid (FTHA)-PET images (lower panel) are used to evaluate both glucose and fatty acid metabolism in PAH patients and correlate metabolism with both RV function and the severity of PAH, When the patients were categorized into three groups as mild PAH (mPAP < 35 mmHg), moderate PAH (35 ≤ mPAP < 50 mmHg), and severe PAH (mPAP ≥ 50 mmHg). The patients' RVEF and mPAP are reported below the images.

The ratio of glucose to fatty acid uptake increases as pulmonary artery pressure. The FDG uptake in RV relative to the LV is similar to the RV/LV perfusion tracer uptake in the patients with mild and moderate PAH (left and centre panels), while in all patients with severe PAH, FDG uptake is higher in the RV relative to the perfusion uptake (a known marker of hibernation) in the patient with severe PAH (right panel). This is a perfusion/metabolism mismatch in the RV and suggests that there is RV myocardial ischemia or hibernation.

Figure 18:

Teaching Points:

This figure illustrates the main pathological changes in the pulmonary vasculature and right ventricle (RV) in PAH. Pulmonary vascular remodeling includes: plexiform lesions, thrombosis, intimal fibrosis, medial thickening. Right ventricular remodeling has two steps: adaptive RV hypertension (RVH) and maladaptive RVH.

Figure 21:

Teaching Points:

This figure illustrates the Randle cycle in the right ventricular myocyte. This can be applied in the treatment of PAH. By inhibiting beta-fatty acid oxidation (FAO) using ranolazine, RV function can be improved and glucose oxidation can be increased.

Figure 22:

Teaching Points:

This figure illustrates the application of inhibiting PDK in the treatment of PAH. Dichloroacetate (DCA) is a small molecular inhibitor of PDK which increases PDH activity thus promoting glucose oxidation. It improves right ventricular hypertrophy caused by pulmonary hypertension.

Figure 24:

Teaching Points:

 

This figure illustrates the molecular mechanisms related to mitochondria which contribute to the pathogenesis of PAH. Changes in upstream regulators of mitochondrial mediators contribute to the dysregulation of mitochondrial mediator proteins and result in excessive mitochondrial fragmentation, aerobic glycolysis, increased proliferation and decreased apoptosis, and decreased mitochondrial biogenesis.


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Asish Dasgupta, Danchen Wu, Lian Tian, Ping Yu Xiong, Kimberly J. Dunham‐Snary, Kuang‐Hueih Chen, Elahe Alizadeh, Mehras Motamed, François Potus, Charles C.T. Hindmarch, Stephen L. Archer. Mitochondria in the Pulmonary Vasculature in Health and Disease: Oxygen‐Sensing, Metabolism, and Dynamics. Compr Physiol 2020, 10: 713-765. doi: 10.1002/cphy.c190027