Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent pathway of apoptosis
Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent pathway of apoptosis
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DOI：
10.1101/407098
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Hideaki Tanaka;Tomohiko Okazaki;Mutsumi Yokota;M. Koike;Y. Okada;Y. Fujiki;Y. Gotoh
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文献类型：
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作者：
Hideaki Tanaka;Tomohiko Okazaki;Mutsumi Yokota;M. Koike;Y. Okada;Y. Fujiki;Y. Gotoh
我们揭示了一个以前未被认识到的过氧化物酶体在线粒体分裂融合动力学、线粒体依赖的半胱天冬酶激活和细胞凋亡的调节中的作用。过氧化物酶体与线粒体共同参与细胞代谢功能，如脂肪酸氧化和氧化还原稳态的维持。然而，过氧化物酶体是否也调节线粒体分裂融合动力学或线粒体依赖性细胞凋亡尚不清楚。我们现在表明，基因消融对过氧化物酶体的生物发生至关重要的过氧化物蛋白Pex3或Pex5，导致小鼠胚胎成纤维细胞（mef）的线粒体断裂，其方式依赖于动力蛋白相关蛋白1 （Drp1）。相反，用过氧化物酶体增殖诱导剂4-苯基丁酸处理后，野生型mef的线粒体延长，但在缺乏pex3的mef中没有。我们进一步发现，在基础条件下，过氧化物酶体缺乏会增加胞浆细胞色素c水平和半胱天冬酶活性，而不会诱导细胞凋亡。它还大大增强依托泊苷诱导的caspase激活和凋亡，表明细胞对死亡信号的敏感性增强。总之，我们的数据揭示了过氧化物酶体在线粒体动力学和线粒体依赖性细胞凋亡调节中的先前未被认识到的作用。鉴于过氧化物酶基因突变可导致致命性疾病，如齐薇格综合征，这种突变对线粒体依赖性细胞凋亡的影响可能有助于疾病的发病机制。
Summary Statements We unveil a previously unrecognized role of peroxisomes in the regulation of mitochondrial fission-fusion dynamics, mitochondrion-dependent caspase activation, and cellular apoptosis. Abstract Peroxisomes cooperate with mitochondria in the performance of cellular metabolic functions such as fatty acid oxidation and maintenance of redox homeostasis. Whether peroxisomes also regulate mitochondrial fission-fusion dynamics or mitochondrion-dependent apoptosis has remained unclear, however. We now show that genetic ablation of the peroxins Pex3 or Pex5, which are essential for peroxisome biogenesis, resulted in mitochondrial fragmentation in mouse embryonic fibroblasts (MEFs) in a manner dependent on dynamin-related protein 1 (Drp1). Conversely, treatment with 4-phenylbutyric acid, an inducer of peroxisome proliferation, resulted in mitochondrial elongation in wild-type MEFs, but not in Pex3-deficient MEFs. We further found that peroxisome deficiency increased the levels of cytosolic cytochrome c and caspase activity under basal conditions without inducing apoptosis. It also greatly enhanced etoposide-induced caspase activation and apoptosis, indicative of an enhanced cellular sensitivity to death signals. Together, our data unveil a previously unrecognized role of peroxisomes in the regulation of mitochondrial dynamics and mitochondrion-dependent apoptosis. Given that mutations of peroxin genes are responsible for lethal disorders such as Zellweger syndrome, effects of such mutations on mitochondrion-dependent apoptosis may contribute to disease pathogenesis.