College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter EX4 4QD, UK.
Institute of Neuroanatomy, Mannheim Centre for Translational Neuroscience, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Cells. 2022 Jun 14;11(12):1922. doi: 10.3390/cells11121922.
Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane-shaping protein PEX11β and division proteins, such as the membrane adaptors FIS1 and MFF, which recruit the fission GTPase DRP1 to the peroxisomal membrane. The latter proteins are also involved in mitochondrial division. Patients with loss of DRP1, MFF or PEX11β function have been identified, showing abnormalities in peroxisomal (and, for the shared proteins, mitochondrial) dynamics as well as developmental and neurological defects, whereas the metabolic functions of the organelles are often unaffected. Here, we provide a timely update on peroxisomal membrane dynamics with a particular focus on peroxisome formation by membrane growth and division. We address the function of PEX11β in these processes, as well as the role of peroxisome-ER contacts in lipid transfer for peroxisomal membrane expansion. Furthermore, we summarize the clinical phenotypes and pathophysiology of patients with defects in the key division proteins DRP1, MFF, and PEX11β as well as in the peroxisome-ER tether ACBD5. Potential therapeutic strategies for these rare disorders with limited treatment options are discussed.
过氧化物酶体是高度动态和响应性的细胞器，可根据细胞需求调整其形态、数量、细胞内位置和代谢功能。哺乳动物细胞中过氧化物酶体的增殖涉及膜成形蛋白 PEX11β 和分裂蛋白（如膜接头 FIS1 和 MFF）的协同作用，它们将分裂 GTP 酶 DRP1 募集到过氧化物酶体膜上。这些蛋白质也参与线粒体分裂。已经鉴定出缺乏 DRP1、MFF 或 PEX11β 功能的患者，显示出过氧化物酶体（和共享蛋白质的线粒体）动力学以及发育和神经缺陷异常，而细胞器的代谢功能通常不受影响。在这里，我们提供了一个关于过氧化物酶体膜动力学的及时更新，特别关注膜生长和分裂引起的过氧化物酶体形成。我们讨论了 PEX11β 在这些过程中的功能，以及过氧化物酶体-内质网接触在过氧化物酶体膜扩展中的脂质转移中的作用。此外，我们总结了关键分裂蛋白 DRP1、MFF 和 PEX11β 以及过氧化物酶体-内质网系链蛋白 ACBD5 缺陷患者的临床表型和病理生理学。对于这些治疗选择有限的罕见疾病，讨论了潜在的治疗策略。
