Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
Present address: Department of Chemistry (Biochemistry Division) Crosley Tower, University of Cincinnati, Cincinnati, Ohio, 45221, USA.
Cell Commun Signal. 2024 Feb 21;22(1):142. doi: 10.1186/s12964-024-01524-x.
Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes, which are involved in fatty acid oxidation and scavenges the result reactive oxygen species (ROS), remains elusive. In addition, impaired peroxisomal ROS inhibit the mammalian target of rapamycin complex 1 (mTORC1) and promote autophagy. Under stress, autophagy serves as a protective mechanism to avoid cell death. In response to oxidative stress, lysosomal calcium mediates transcription factor EB (TFEB) activation. However, the impact of calcium on peroxisome function and the mechanisms governing cellular homeostasis to prevent diseases caused by calcium deficiency are currently unknown.
To investigate the significance of calcium in peroxisomes and their roles in preserving cellular homeostasis, we established an in-vitro scenario of calcium depletion.
This study demonstrated that calcium deficiency reduces catalase activity, resulting in increased ROS accumulation in peroxisomes. This, in turn, inhibits mTORC1 and induces pexophagy through TFEB activation. However, treatment with the antioxidant N-acetyl-l-cysteine (NAC) and the autophagy inhibitor chloroquine impeded the nuclear translocation of TFEB and attenuated peroxisome degradation.
Collectively, our study revealed that ROS-mediated TFEB activation triggers pexophagy during calcium deficiency, primarily because of attenuated catalase activity. We posit that calcium plays a significant role in the proper functioning of peroxisomes, critical for fatty-acid oxidation and ROS scavenging in maintaining cellular homeostasis. These findings have important implications for signaling mechanisms in various pathologies, including Zellweger's syndrome and ageing.
钙是一种普遍存在的细胞内信使，调节参与细胞增殖、分化和运动的各种基因的表达。已经提出了钙参与各种代谢途径的可能性。然而，钙在过氧化物酶体中的作用仍然难以捉摸，过氧化物酶体参与脂肪酸氧化，并清除活性氧（ROS）。此外，受损的过氧化物酶体抑制哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）并促进自噬。在应激下，自噬作为一种保护机制，以避免细胞死亡。在氧化应激下，溶酶体钙介导转录因子 EB（TFEB）的激活。然而，钙对过氧化物酶体功能的影响以及控制细胞内稳态以防止因钙缺乏引起的疾病的机制目前尚不清楚。
为了研究钙在过氧化物酶体中的意义及其在维持细胞内稳态中的作用，我们建立了体外钙耗竭的场景。
本研究表明，钙缺乏会降低过氧化氢酶的活性，导致过氧化物酶体中 ROS 积累增加。这反过来又抑制 mTORC1，并通过 TFEB 的激活诱导pexophagy。然而，抗氧化剂 N-乙酰-l-半胱氨酸（NAC）和自噬抑制剂氯喹的处理阻止了 TFEB 的核易位，并减弱了过氧化物酶体的降解。
总的来说，我们的研究表明，ROS 介导的 TFEB 激活在钙缺乏时触发 pexophagy，主要是由于过氧化氢酶活性降低。我们假设钙在过氧化物酶体的正常功能中起着重要作用，这对于维持细胞内稳态的脂肪酸氧化和 ROS 清除至关重要。这些发现对包括 Zellweger 综合征和衰老在内的各种病理中的信号转导机制具有重要意义。
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