In health, MiDs regulate Drp1-mediated fission, whereas in disease, epigenetic upregulation of MiDs increases mitotic fission, which drives pathological proliferation and apoptosis resistance. The miR-34a-3p-MiD pathway offers new therapeutic targets for PAH.

Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1a, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic PO 2 without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the

Right ventricular (RV) function determines prognosis in pulmonary arterial hypertension (PAH). We hypothesize that ischemia causes RV dysfunction in PAH by triggering dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. RV function was compared in control rats (n=50) versus rats with monocrotaline-induced PAH (MCT- PAH; n=60) both in vivo (echocardiography) and ex vivo (RV Langendorff). Mitochondrial membrane potential and morphology and RV function were assessed before or after two cycles of ischemia-reperfusion injury challenge (RV-IR). The effects of Mdivi-1 (25 μM), a Drp1 GTPase inhibitor and P110 (1 μM), a peptide inhibitor of Drp1–Fis1 interaction were studied. We found that MCT caused RV hypertrophy, RV vascular rarefaction and RV dysfunction. Prior to IR, the mitochondria in MCT-PAH RV were depolarized and swollen with increased Drp1 content and reduced aconitase activity. RV-IR increased RV end diastolic pressure (RVEDP) and mitochondrial Drp1 expression in both control and MCT-PAH RVs. IR depolarized mitochondria in control RV but did not exacerbate the basally depolarized MCT-PAH RV mitochondria. During RV IR mdivi-1 and P110 reduced Drp1 translocation to mitochondria, improved mitochondrial structure and function, and reduced RVEDP. In conclusion, RV ischemia occurs in PAH and causes Drp1-Fis1-mediated fission leading to diastolic dysfunction. Inhibition of mitochondrial fission preserves RV function in RV-IR.

These results highlight miR-mediated MCUC dysfunction as a unifying mechanism in PAH that can be therapeutically targeted.

Synopsis Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mitochondrial DNA (mtDNA) sequence variation contributes to disease susceptibility. In this study we present a novel animal model of mtDNA polymorphisms, the mitochondrial nuclear exchange mouse (MNX), in which the mtDNA from C3H/HeN mouse has been inserted onto the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harboring the C57/BL6J mtDNA generate more reactive oxygen species (ROS) and have a higher mitochondrial membrane potential relative to those having the C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the “mitochondrial paradigm” for the development of disease susceptibility, and show that the mtDNA modulates, cellular bioenergetics, mitochondrial reactive oxygen species generation and susceptibility to cardiac stress.