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，学界对线粒体周转的激素调控机制仍认知有限。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明确。本研究通过体外与体内肝细胞模型开展实验，证实T3诱导的线粒体自噬与氧化磷酸化及活性氧生成紧密耦联。研究结果显示，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（calcium/calmodulin-dependent protein kinase kinase 2, β, CAMKK2），介导5'腺苷单磷酸活化蛋白激酶（5' AMP-activated protein kinase, PRKAA1/AMPK）的磷酸化；后者进一步磷酸化UNC-51样自噬激活激酶1（unc-51 like autophagy activating kinase 1, ULK1），促使其向线粒体募集并启动线粒体自噬。此外，在经T3处理的细胞中敲除ULK1，会同时损害线粒体自噬与氧化磷酸化功能，但不会影响T3诱导的常规自噬/脂噬过程。本研究揭示了一条全新的ROS-AMPK-ULK1信号通路，将T3诱导的线粒体周转与线粒体活性相耦联，表明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。