Mitochondrial succinate dehydrogenase function is essential for sperm motility and male fertility

AimChronic hypoxia is a common cause of pulmonary hypertension (PH). We test the hypothesis that microRNA‐210 (miR‐210) mediates hypoxia‐induced PH by targeting mitochondrial metabolism and increasing reactive oxygen species (mtROS) production in the lungs.MethodsAdult wildtype (WT) or miR‐210 knockout (KO) mice were exposed to hypoxia (10.5% O2) or normoxia for 4 weeks. We measured miR‐210 levels, right ventricular systolic pressure (RVSP), and histological changes in heart and lung tissues. Mitochondrial bioenergetics and mtROS production were assessed in isolated lung mitochondria.ResultsHypoxia increased right ventricular wall thickness and pulmonary vessel wall muscularization in WT, but not miR‐210 KO mice. No sex differences were observed. In male mice, hypoxia increased miR‐210 levels in the lung and RVSP, which were abrogated by miR‐210 deficiency. Hypoxia upregulated mitochondrial oxygen consumption rate and mtROS flux, which were negated in miR‐210 KO animals. In addition, chronic hypoxia increased macrophage accumulation in lungs of WT, but not miR‐210 KO mice. Moreover, miR‐210 overexpression in lungs of WT animals recapitulated the effects of hypoxia and increased mitochondrial oxygen consumption rate, mtROS flux, right ventricular wall thickness, pulmonary vessel wall muscularization and RVSP. MitoQ revoked the effects of miR‐210 on lung mitochondrial bioenergetics, right ventricular and pulmonary vessel remodeling and RVSP.ConclusionOur findings with loss‐of‐function and gain‐of‐function approaches provide explicit evidence that miR‐210 mediates hypoxia‐induced PH by upregulating mitochondrial bioenergetics and mtROS production in a murine model, revealing new insights into the mechanisms and therapeutic targets for treatment of PH.

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Mitochondrial succinate dehydrogenase function is essential for sperm motility and male fertility

Cited by 4 publications

References 94 publications

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MicroRNA‐210 mediates hypoxia‐induced pulmonary hypertension by targeting mitochondrial bioenergetics and mtROS flux

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