Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Mol Genet Metab. 2021 May;133(1):83-93. doi: 10.1016/j.ymgme.2021.03.005. Epub 2021 Mar 11.
Leigh syndrome is a severe mitochondrial neurodegenerative disease with no effective treatment. In the Ndufs4 mouse model of Leigh syndrome, continuously breathing 11% O (hypoxia) prevents neurodegeneration and leads to a dramatic extension (~5-fold) in lifespan. We investigated the effect of hypoxia on the brain metabolism of Ndufs4 mice by studying blood gas tensions and metabolite levels in simultaneously sampled arterial and cerebral internal jugular venous (IJV) blood. Relatively healthy Ndufs4 and wildtype (WT) mice breathing air until postnatal age ~38 d were compared to Ndufs4 and WT mice breathing air until ~38 days old followed by 4-weeks of breathing 11% O. Compared to WT control mice, Ndufs4 mice breathing air have reduced brain O consumption as evidenced by an elevated partial pressure of O in IJV blood (PO) despite a normal PO in arterial blood, and higher lactate/pyruvate (L/P) ratios in IJV plasma revealed by metabolic profiling. In Ndufs4 mice, hypoxia treatment normalized the cerebral venous PO and L/P ratios, and decreased levels of nicotinate in IJV plasma. Brain concentrations of nicotinamide adenine dinucleotide (NAD) were lower in Ndufs4 mice breathing air than in WT mice, but preserved at WT levels with hypoxia treatment. Although mild hypoxia (17% O) has been shown to be an ineffective therapy for Ndufs4 mice, we find that when combined with nicotinic acid supplementation it provides a modest improvement in neurodegeneration and lifespan. Therapies targeting both brain hyperoxia and NAD deficiency may hold promise for treating Leigh syndrome.
Leigh 综合征是一种严重的线粒体神经退行性疾病，目前尚无有效的治疗方法。在 Leigh 综合征的 Ndufs4 小鼠模型中，持续呼吸 11%的氧气（低氧）可防止神经退行性变，并使寿命显著延长（约 5 倍）。我们通过研究同时采集的动脉和颈内静脉（IJV）血的血气张力和代谢物水平，研究了低氧对 Ndufs4 小鼠大脑代谢的影响。我们比较了持续呼吸空气至出生后约 38 天的相对健康的 Ndufs4 和野生型（WT）小鼠与持续呼吸空气至 38 天左右，然后呼吸 11%氧气 4 周的 Ndufs4 和 WT 小鼠。与 WT 对照小鼠相比，呼吸空气的 Ndufs4 小鼠的脑耗氧量降低，这表现为 IJV 血中氧气分压（PO）升高，尽管动脉血中的 PO 正常，IJV 血浆中的乳酸/丙酮酸（L/P）比值升高表明代谢谱分析。在 Ndufs4 小鼠中，低氧处理使脑静脉 PO 和 L/P 比值正常化，并降低了 IJV 血浆中的烟碱酸水平。与呼吸空气的 WT 小鼠相比，呼吸空气的 Ndufs4 小鼠大脑中的烟酰胺腺嘌呤二核苷酸（NAD）浓度较低，但低氧处理可将其保持在 WT 水平。尽管轻度低氧（17%O）已被证明对 Ndufs4 小鼠无效，但我们发现，当与烟碱酸补充相结合时，它可适度改善神经退行性变和寿命。针对脑过度氧合和 NAD 缺乏的治疗方法可能为 Leigh 综合征的治疗带来希望。
