Verhoeven Nicolas, Oshima Yumiko, Cartier Etienne, Bippes Claudia Christiane, Neutzner Albert, Boyman Liron, Karbowski Mariusz
Center for Biomedical Engineering and Technology, University Hospital Basel, University of Basel, Basel, Switzerland; Department of Biochemistry and Molecular Biology, University Hospital Basel, University of Basel, Basel, Switzerland.
Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
Dev Cell. 2025 Jan 6;60(1):40-50.e5. doi: 10.1016/j.devcel.2024.09.010. Epub 2024 Oct 17.
We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. In human immortalized cells, MARCH5 knockout leads to the accumulation of immature peroxisomes, reduced fatty-acid-induced peroxisomal biogenesis, and abnormal peroxisome biogenesis in MARCH5/Pex14 and MARCH5/Pex3 dko cells. Upon fatty-acid-induced peroxisomal biogenesis, MARCH5 redistributes to peroxisomes, and ubiquitination activity-deficient mutants of MARCH5 accumulate on peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Similarly, depletion of peroxisome biogenesis factor Pex14 leads to the accumulation of MARCH5- and Tom20-positive pre-peroxisomes, whereas no peroxisomes are detected in MARCH5/Pex14 dko cells. Inconsistent with MARCH5 merely acting as a quality factor, mitochondrial decline is not evident in tested models. Furthermore, reduced expression of peroxisomal proteins is detected in MARCH5 cells, whereas some of these proteins are stabilized in peroxisome biogenesis deficiency models lacking MARCH5 expression. Thus, MARCH5 is central for mitochondria-dependent peroxisome biogenesis.
我们报告称，线粒体外膜（OMM）相关的E3泛素连接酶MARCH5对于产生线粒体衍生的前过氧化物酶体至关重要。在人类永生化细胞中，MARCH5基因敲除导致未成熟过氧化物酶体的积累、脂肪酸诱导的过氧化物酶体生物发生减少，以及MARCH5/Pex14和MARCH5/Pex3双敲除细胞中过氧化物酶体生物发生异常。在脂肪酸诱导的过氧化物酶体生物发生过程中，MARCH5重新分布到过氧化物酶体，且MARCH5的泛素化活性缺陷突变体在含有高水平OMM蛋白Tom20（线粒体衍生的前过氧化物酶体）的过氧化物酶体上积累。同样，过氧化物酶体生物发生因子Pex14的缺失导致MARCH5和Tom20阳性前过氧化物酶体的积累，而在MARCH5/Pex14双敲除细胞中未检测到过氧化物酶体。与MARCH5仅作为质量因子的作用不一致，在所测试的模型中线粒体衰退并不明显。此外，在MARCH5缺失的细胞中检测到过氧化物酶体蛋白的表达降低，而在缺乏MARCH5表达的过氧化物酶体生物发生缺陷模型中，其中一些蛋白则得到稳定。因此，MARCH5对于线粒体依赖性过氧化物酶体生物发生至关重要。
