Enhanced Mitochondrial Mrs2-Mg2+ Signaling Drives Mitochondrial Dysfunction in Pulmonary Arterial Hypertension Rats - PubMed
3 hours ago
- #mitochondrial dysfunction
- #ionic homeostasis
- #PAH
- Pulmonary arterial hypertension (PAH) involves ionic homeostasis and vascular remodeling.
- Cytosolic magnesium ([Mg2+]���) depletion is a hallmark of PAH, but mitochondrial Mg2+ (mMg2+) role was unclear.
- Mrs2, the primary mMg2+ influx transporter, is hypothesized to drive PAH by causing mitochondrial ionic imbalance.
- In PAH-pulmonary arterial smooth muscle cells, Mrs2 upregulation and Slc41a3 downregulation led to mMg2+ overload and [Mg2+]��� depletion.
- Excess mMg2+ promoted pyruvate dehydrogenase phosphorylation, driving glycolysis and lactate production linked to HIF-1α activation.
- Proinflammatory cytokines amplified lactate accumulation, worsening mMg2+ and cytosolic calcium ([Ca2+]���) overload, forming a maladaptive feedback loop.
- This ionic-metabolic stress triggered mitochondrial fission, redox imbalance, and pulmonary arterial smooth muscle cell hyperproliferation.
- Mrs2 knockdown restored mitochondrial bioenergetics, attenuated vascular remodeling, and improved hemodynamics in PAH rats.
- Targeting Mrs2-mediated mMg2+ signaling may represent a potential therapeutic approach for PAH.