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

Pulmonary arterial hypertension (PAH) involves ionic homeostasis and vascular remodeling. While cytosolic magnesium ([Mg²⁺]ᵢ) depletion is a hallmark of PAH, the role of mitochondrial Mg²⁺ (_mMg²⁺) remains elusive. mitochondrial RNA splicing 2 (Mrs2), the primary _mMg²⁺ influx transporter, is hypothesized to drive PAH by orchestrating mitochondrial ionic imbalance and dysfunction.

Primary pulmonary arterial smooth muscle cells isolated from monocrotaline-induced PAH rats were used for mechanistic investigation, with key metabolic and mitochondrial alterations validated in the Su5416 (semaxanib)/hypoxia model. In vivo, adeno-associated virus-mediated Mrs2 knockdown was used to evaluate therapeutic potential.

In PAH-pulmonary arterial smooth muscle cells, Mrs2 upregulation and Slc41a3 (solute carrier family 41 member 3) downregulation caused _mMg²⁺ overload and [Mg²⁺]ᵢ depletion. Excess _mMg²⁺ promoted pyruvate dehydrogenase phosphorylation, driving glycolysis and lactate production in association with Hif-1α (hypoxia-inducible factor-1α) activation and a Pkm2 (pyruvate kinase M2)-linked glycolytic shift. Proinflammatory cytokines further amplified lactate accumulation, which exacerbated _mMg²⁺ and cytosolic calcium ([Ca²⁺]ᵢ) overload, establishing a maladaptive _mMg²⁺-lactate feedback loop. This ionic-metabolic stress triggered Ca²⁺-dependent mitochondrial fission, redox imbalance, and pulmonary arterial smooth muscle cell hyperproliferation. Moreover, Mrs2 was associated with enhanced Trpc3 (transient receptor potential channel 3)-dependent mitochondrial Ca²⁺ uptake. Crucially, Mrs2 knockdown restored mitochondrial bioenergetics and morphology, attenuated vascular remodeling, and improved hemodynamics in monocrotaline-PAH rats.

Aberrant Mrs2-mediated _mMg²⁺ signaling disrupts global ionic and metabolic homeostasis, driving mitochondrial dysfunction and pathogenic remodeling in PAH. Targeting the Mrs2-centered ionic-metabolic-dynamic axis may represent a potential therapeutic approach that warrants further investigation to interrupt PAH progression.