Enhanced Mitochondrial Mrs2-Mg²⁺ Signaling Drives Mitochondrial Dysfunction in Pulmonary Arterial Hypertension Rats

Area of Science:

• Cardiovascular Biology
• Mitochondrial Physiology
• Cellular Metabolism

Background:

• Pulmonary arterial hypertension (PAH) is characterized by ionic imbalance and vascular remodeling.
• Cytosolic magnesium ([Mg2+]i) depletion is a known feature of PAH, but the role of mitochondrial magnesium (mMg2+) is unclear.
• Mitochondrial RNA splicing 2 (Mrs2) is the primary transporter for mMg2+ influx and is hypothesized to be involved in PAH pathogenesis.

Purpose of the Study:

• To investigate the role of Mrs2 in mitochondrial magnesium homeostasis and its contribution to PAH.
• To elucidate the mechanisms by which Mrs2-mediated mMg2+ dysregulation affects cellular metabolism and vascular remodeling in PAH.
• To evaluate the therapeutic potential of targeting Mrs2 in PAH.

Main Methods:

• Mechanistic studies using primary pulmonary arterial smooth muscle cells from monocrotaline-induced PAH rats.
• Validation of metabolic and mitochondrial alterations in the Su5416/hypoxia model.
• In vivo assessment of adeno-associated virus-mediated Mrs2 knockdown in monocrotaline-PAH rats.

Main Results:

• Mrs2 upregulation and Slc41a3 downregulation in PAH cells led to mMg2+ overload and [Mg2+]i depletion.
• Excess mMg2+ promoted glycolysis via pyruvate dehydrogenase phosphorylation and HIF-1α activation.
• A feedback loop between mMg2+, lactate, and cytosolic calcium ([Ca2+]i) overload exacerbated mitochondrial dysfunction, promoting cell hyperproliferation and vascular remodeling.
• Mrs2 knockdown reversed these detrimental effects, restoring mitochondrial function and improving hemodynamics in PAH rats.

Conclusions:

• Aberrant Mrs2-mediated mMg2+ signaling disrupts ionic and metabolic homeostasis, driving mitochondrial dysfunction and PAH.
• Targeting the Mrs2-centered axis presents a potential therapeutic strategy for interrupting PAH progression.