Targeting Mitochondrial Metabolic Dysfunction in Pulmonary Hypertension: Toward New Therapeutic Approaches?

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling leading to right heart failure and death. To date, despite the three therapeutic approaches targeting the three major endothelial dysfunction pathways based on the prostacyclin, nitric oxide/cyclic guanosine monophosphate, and endothelin pathways, PAH remains a serious disease. As such, new targets and therapeutic agents are needed. Mitochondrial metabolic dysfunction is one of the mechanisms involved in PAH pathogenesis in part through the induction of a Warburg metabolic state of enhanced glycolysis but also through the upregulation of glutaminolysis, tricarboxylic cycle and electron transport chain dysfunction, dysregulation of fatty acid oxidation or mitochondrial dynamics alterations. The aim of this review is to shed light on the main mitochondrial metabolic pathways involved in PAH and to provide an update on the resulting interesting potential therapeutic perspectives.

Mitochondrial dysfunction drives the pathogenesis of pulmonary arterial hypertension: insights from a multi-omics investigation

“…Citrate is a signi cant intermediate produced in the initial step of the citric acid cycle, subsequently undergoing conversion into isocitrate (52). Dysfunction of the citric acid cycle has been reported to occur in PAH and might potentially contribute to the pathogenesis of PAH (29). In addition, increased levels of 3-phenyllactic-acid were found in the PAH samples in the current study.…”

“…Increased levels of citric acid cycle intermediates have been found in PAH patients compared with healthy subjects, suggesting possible dysfunction of mitochondrial citric acid cycle in PAH (32). In addition, altered mitochondrial dynamics such as ssion/fusion imbalance could promote the proliferation phenotype in pulmonary arterial cells (29). Nevertheless, the exact roles of mitochondrial abnormalities in the progression of PAH remain incompletely understood.…”

“…Mitochondrial dysfunction has been implicated in the pathogenesis and progression in a wide range of diseases, such as Alzheimer's disease, chronic lung diseases, and various malignancies (26-28). It also plays an important role in PAH pathophysiology (29). Compared with healthy pulmonary artery smooth muscle cells (PASMCs), human PAH PASMCs have hyperpolarized mitochondria and decreased mitochondria-derived reactive oxygen species (30,31).…”

Mechanisms of Pulmonary Vasculopathy in Acute and Long-Term COVID-19: A Review

“…In addition, oxidative stress and mitochondrial dysfunction are involved in the endothelial dysfunction observed in acute COVID-19 [142,143] and may contribute to long COVID [144]. Interestingly, as mitochondrial dysfunction is involved in pulmonary vascular remodeling and endothelial dysfunction in PAH, it may be another potential mechanism of long-term pulmonary sequelae after COVID-19 [145,146].…”

Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

“…Since MQC, i.e., the regulation and maintenance of mitochondrial homeostasis, is essential not only for the fine-tuning of cell energy production [115] but also for overall cellular health, mitochondrial dysfunction and inadequate QC inevitably lead to metabolic disorders in many pathological conditions [116,117]. Defective MQC has been associated with diseases of the heart [118], lung [119,120], and kidneys [121], and in neuronal and muscular disorders [122]. Further, the metabolic switch from ATP production by oxidative phosphorylation to aerobic glycolysis (the Warburg effect) is one of the underlining mechanisms of cancer cell proliferation, allowing transformed cells to adjust and grow in a poorly oxygenated milieu [123].…”