Organelles in focus
Mitochondria: Roles in pulmonary hypertension

https://doi.org/10.1016/j.biocel.2014.08.012Get rights and content

Abstract

Mitochondria are essential cell organelles responsible for ATP production in the presence of oxygen. In the pulmonary vasculature, mitochondria contribute to physiological intracellular signalling pathways through production of reactive oxygen species and play the role of oxygen sensors that coordinate hypoxic pulmonary vasoconstriction. Mitochondria also play a pathophysiological role in pulmonary hypertension (PH). This disease is characterized by increased pulmonary arterial pressure and remodelling of pulmonary arteries, leading to increased pulmonary vascular resistance, hypertrophy of the right ventricle, right heart failure and ultimately death. Mitochondrial alterations have been evidenced in PH in pulmonary arteries and in the right ventricle, in particular a chronic shift in energy production from mitochondrial oxidative phosphorylation to glycolysis. This shift, initially described in cancer cells, may play a central role in PH pathogenesis. Further studies of these metabolic mitochondrial alterations in PH may therefore open new therapeutic perspectives in this disease.

Section snippets

Organelle facts

  • •

    Mitochondria play essential physiological roles in the pulmonary vasculature, through oxygen sensing and production of reactive oxygen species.

  • •

    Mitochondrial dysfunction plays a role in pathogenesis of pulmonary hypertension (PH).

  • •

    Suppression of glucose oxidation and subsequent increase in glycolysis has been evidenced in PH in all pulmonary arterial layers (endothelium, smooth muscle and adventitia) and in the remodelled right ventricle.

  • •

    Several intra- and extra-mitochondrial causes of

Introduction and organelle function

In eukaryotic cells, mitochondria are essential organelles that produce energy through oxidative phosphorylation. Mitochondria provide metabolites for synthesis of fatty acids and carbohydrates in proliferating cells, but can also, if necessary, initiate apoptosis to maintain homeostasis (Zamzami and Kroemer, 2001). In the pulmonary vasculature, mitochondria are a physiological source of reactive oxygen species (ROS) (Freund-Michel et al., 2013), and play the role of oxygen sensors that

Cell physiology

In pulmonary vascular cells, as in other cells, mitochondria are providers of adenosine 5′-triphosphate (ATP) (Fig. 1). On one hand, after its cellular uptake, glucose is transformed into pyruvate by cytoplasmic glycolysis. Pyruvate enters the mitochondria and is transformed into acetyl-CoA by pyruvate dehydrogenase (PDH). On the other hand, fatty acids transported into cells undergo β-oxidation to produce acetyl-CoA as well. Acetyl-CoA enters the Krebs cycle which produces the electron donors

Organelle pathology

PH is characterised by increased pulmonary arterial pressure and remodelling of pulmonary arteries. Increased resistance in these vessels causes hypertrophy of the right ventricle (RV), whose function progressively declines and leads to right heart failure and ultimately death (Montani et al., 2013). Mitochondrial abnormalities have been evidenced in pulmonary arteries and in the RV and may therefore play a major role in this disease (Fig. 2).

Conclusion and future outlook

Mitochondrial dysfunction is observed in PH, both in remodelled RV and pulmonary arteries, but with different triggering mechanisms. In pulmonary arteries, various intra- and extramitochondrial causes have been described. In the heart, mitochondrial dysfunction is triggered by ischemia due to low coronary arterial flow and angiogenesis decrease. However, these different mechanisms all lead to the same metabolic abnormality: reduction of mitochondrial glucose oxidation towards glycolysis.

References (47)

  • S. Bonnet et al.

    The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted

    Proc Natl Acad Sci USA

    (2007)
  • P. Crosswhite et al.

    Molecular mechanisms of pulmonary arterial remodelling

    Mol Med

    (2014)
  • P. Dromparis et al.

    Mitochondria in vascular health and disease

    Annu Rev Physiol

    (2013)
  • P. Dromparis et al.

    Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension

    Circulation

    (2013)
  • P. Dromparis et al.

    Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodelling and pulmonary hypertension

    Circ Res

    (2013)
  • P. Dromparis et al.

    The role of mitochondria in pulmonary vascular remodelling

    J Mol Med (Berl)

    (2010)
  • E. Dumas de La Roque et al.

    Dehydroepiandrosterone reverses chronic hypoxia/reoxygenation-induced right ventricular dysfunction in rats

    Eur Respir J

    (2012)
  • Y.H. Fang et al.

    Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle's cycle

    J Mol Med (Berl)

    (2012)
  • V. Freund-Michel et al.

    Reactive oxygen species as therapeutic targets in pulmonary hypertension

    Ther Adv Respir Dis

    (2013)
  • J. Gomez-Arroyo et al.

    Metabolic gene remodelling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension

    Circ Heart Fail

    (2013)
  • G. Marsboom et al.

    Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension

    Circ Res

    (2012)
  • M.S. McMurtry et al.

    Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis

    Circ Res

    (2004)
  • D. Montani et al.

    Pulmonary arterial hypertension

    Orphanet J Rare Dis

    (2013)

    • Cited by (44)

    • Melatonin activates the Mst1-Nrf2 signaling to alleviate cardiac hypertrophy in pulmonary arterial hypertension

      2022, European Journal of Pharmacology
      Citation Excerpt :

      Increasing numbers of studies have shown that oxidative stress is predominantly involved in RV remodeling, entailing multiple pathological changes, such as fibrosis, hypertrophy, and heart failure (Rawat et al., 2016; Roh and Choi, 2016). Cardiac tissue contains abundant mitochondria, and mitochondrial alterations and dysfunction, resulting from ROS-induced inactivation of important mitochondrial components, have been noted to occur in RV PAH (Freund-Michel et al., 2014; Venditti et al., 2013). Melatonin (Mel; N-acetyl-5-methoxytryptamine), an endogenously-produced indolamine, has been shown to act as a potent antioxidant, being able to exert protective effects against various cardiovascular diseases, such as ischemia/reperfusion injury, diabetic cardiomyopathy, and myocardial hypertrophy (Pei et al., 2017; Reiter et al., 2016).

    • miR-150-PTPMT1-cardiolipin signaling in pulmonary arterial hypertension

      2021, Molecular Therapy Nucleic Acids
      Citation Excerpt :

      The converging effects of hypoxia, inflammation, and oxidative and metabolic stress play a key contributory role. At the cellular level, the arterial and right ventricular (RV) remodeling in PAH is associated with a shift from oxidative phosphorylation to glycolysis,3 which increases the availability of non-oxidized lipids, amino acids, and sugars essential for rapid cell proliferation.4 These changes are accompanied by inhibition of mitochondrial biogenesis, mitochondrial fragmentation, membrane hyperpolarization, and altered reactive oxygen species (ROS) production.4,5

    • Making a case for metallothioneins conferring cardioprotection in pulmonary hypertension

      2020, Medical Hypotheses
      Citation Excerpt :

      The pathogenesis of PH and right ventricular remodelling [13,15–17], are largely underpinned by mitochondrial dysfunction [18–20]. In particular, mitochondrial pathways are either up or downregulated in PH and right ventricular remodelling [18–20]. For example, apoptosis, a pathway central to the mitochondria, is upregulated in PH and right ventricular remodelling [21–23].

    • Mitochondrial bioenergetics and pulmonary dysfunction: Current progress and future directions

      2020, Paediatric Respiratory Reviews
      Citation Excerpt :

      Two hypotheses, both focused on a critical role of mitochondrial ROS, have been proposed: a) the redox hypothesis in which decreased generation of mitochondrial ROS and reduced redox state initiates hypoxic vasospasm [75] and b) the ROS hypothesis which proposes that hypoxic vasoconstriction is mediated by increased generation of ROS [76]. Vascular remodeling in PH has been closely associated with a metabolic shift from mitochondrial oxidative phosphorylation to anaerobic glycolysis in actively proliferating PASMCs, endothelial cells and fibroblasts [77–79], called the Warburg effect. The Warburg effect confers bioenergetic and biosynthetic advantages to proliferating cells by increasing non-oxidative ATP production [80].

    • Commentary: Mitochondrial respiration in right heart failure

      2020, Journal of Thoracic and Cardiovascular Surgery

    • OP2113, a new drug for chronic hypoxia-induced pulmonary hypertension treatment in rat

      2023, British Journal of Pharmacology
    View all citing articles on Scopus
    View full text
    Copyright © 2014 Elsevier Ltd. All rights reserved.