Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling

Currently, there is limited understanding about hormonal regulation of mitochondrial turnover. Thyroid hormone (T₃) increases oxidative phosphorylation (OXPHOS), which generates reactive oxygen species (ROS) that damage mitochondria. However, the mechanism for maintenance of mitochondrial activity and quality control by this hormone is not known. Here, we used both in vitro and in vivo hepatic cell models to demonstrate that induction of mitophagy by T₃ is coupled to oxidative phosphorylation and ROS production. We show that T₃ induction of ROS activates CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, β) mediated phosphorylation of PRKAA1/AMPK (5′ AMP-activated protein kinase), which in turn phosphorylates ULK1 (unc-51 like autophagy activating kinase 1) leading to its mitochondrial recruitment and initiation of mitophagy. Furthermore, loss of ULK1 in T₃-treated cells impairs both mitophagy as well as OXPHOS without affecting T₃ induced general autophagy/lipophagy. These findings demonstrate a novel ROS-AMPK-ULK1 mechanism that couples T₃-induced mitochondrial turnover with activity, wherein mitophagy is necessary not only for removing damaged mitochondria but also for sustaining efficient OXPHOS.

目前，人们对激素调控线粒体周转的机制尚缺乏深入了解。甲状腺激素（Thyroid hormone, T₃）可增强氧化磷酸化（oxidative phosphorylation, OXPHOS）过程，该过程会产生活性氧（reactive oxygen species, ROS）并造成线粒体损伤。然而，该激素维持线粒体活性与质量控制的具体机制尚未阐明。本研究通过体外及体内肝细胞模型，证实T₃诱导的线粒体自噬（mitophagy）与氧化磷酸化及活性氧生成存在耦联关系。研究发现，T₃诱导产生的活性氧会激活钙/钙调蛋白依赖性蛋白激酶激酶2β（CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2, β）介导的5'腺苷单磷酸活化蛋白激酶（PRKAA1/AMPK, 5′ AMP-activated protein kinase）磷酸化，后者进一步磷酸化UNC-51样自噬激活激酶1（ULK1, unc-51 like autophagy activating kinase 1），促使其向线粒体募集并启动线粒体自噬。此外，在T₃处理的细胞中敲除ULK1会同时损伤线粒体自噬与氧化磷酸化过程，但不会影响T₃诱导的常规自噬/脂噬。本研究结果揭示了一条全新的ROS-AMPK-ULK1通路，该通路可将T₃诱导的线粒体周转与线粒体活性相耦联，即线粒体自噬不仅可清除受损线粒体，同时对维持高效的氧化磷酸化过程至关重要。