Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
Elife. 2022 Apr 25;11:e75143. doi: 10.7554/eLife.75143.
How environmental cues influence peroxisome proliferation, particularly through organelles, remains largely unknown. Yeast peroxisomes metabolize fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, produced by these pathways enter mitochondria for ATP production and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation in Pichia pastoris was abolished in NADH-shuttling- and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by a high AMP/ATP ratio. In OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by the Δgal83 mutant, were rescued by deletion of three transcriptional repressor genes (MIG1, MIG2, and NRG1) controlled by SNF1 signaling. Our results are interpreted in terms of a mechanism by which peroxisomal and mitochondrial proteins and/or metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol, and the nucleus. We discuss the physiological relevance of this work in the context of human OXPHOS deficiencies.
环境线索如何影响过氧化物酶体增殖，特别是通过细胞器，在很大程度上仍然未知。酵母过氧化物酶体代谢脂肪酸（FA），甲醇营养型酵母也代谢甲醇。这些途径产生的 NADH 和乙酰辅酶 A 进入线粒体进行 ATP 产生和合成代谢反应。在 FA 和/或甲醇代谢过程中，线粒体氧化磷酸化（OXPHOS）途径接受 NADH 用于 ATP 产生和维持细胞氧化还原平衡。值得注意的是，影响复合物 I 或 III 的 NADH 穿梭和 OXPHOS 突变体或线粒体解偶联剂 2,4-二硝基苯酚（DNP）使毕赤酵母中的过氧化物酶体增殖完全消失，表明 ATP 耗竭导致表型。我们表明，线粒体 OXPHOS 缺陷抑制几种过氧化物酶体蛋白的表达，这些蛋白涉及 FA 和甲醇代谢，以及过氧化物酶体分裂和增殖。这些基因受 Snf1 复合物（SNF1）调控，该途径通常通过高 AMP/ATP 比激活。在 OXPHOS 突变体中，Snf1 通过磷酸化激活，但与其相互作用的亚基 Gal83 未能转位到核内。在 OXPHOS 突变体中观察到的过氧化物酶体增殖表型缺陷，以及 Δgal83 突变体的表型模拟，通过删除三个受 SNF1 信号控制的转录阻遏基因（MIG1、MIG2 和 NRG1）得到挽救。我们的结果是根据一种机制来解释的，即过氧化物酶体和线粒体蛋白和/或代谢物影响氧化还原和能量代谢，同时也影响过氧化物酶体的发生和增殖，从而例证了涉及过氧化物体、线粒体、细胞质和细胞核的细胞器间通讯和相互作用。我们在人类 OXPHOS 缺陷的背景下讨论了这项工作的生理相关性。
