Branda S S, Cavadini P, Adamec J, Kalousek F, Taroni F, Isaya G
Department of Pediatric and Adolescent Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
J Biol Chem. 1999 Aug 6;274(32):22763-9. doi: 10.1074/jbc.274.32.22763.
Frataxin is a nuclear-encoded mitochondrial protein which is deficient in Friedreich's ataxia, a hereditary neurodegenerative disease. Yeast mutants lacking the yeast frataxin homologue (Yfh1p) show iron accumulation in mitochondria and increased sensitivity to oxidative stress, suggesting that frataxin plays a critical role in mitochondrial iron homeostasis and free radical toxicity. Both Yfh1p and frataxin are synthesized as larger precursor molecules that, upon import into mitochondria, are subject to two proteolytic cleavages, yielding an intermediate and a mature size form. A recent study found that recombinant rat mitochondrial processing peptidase (MPP) cleaves the mouse frataxin precursor to the intermediate but not the mature form (Koutnikova, H., Campuzano, V., and Koenig, M. (1998) Hum. Mol. Gen. 7, 1485-1489), suggesting that a different peptidase might be required for production of mature size frataxin. However, in the present study we show that MPP is solely responsible for maturation of yeast and human frataxin. MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to mature size protein. In this way, MPP could influence frataxin function and indirectly affect mitochondrial iron homeostasis.
铁调素是一种核编码的线粒体蛋白，在遗传性神经退行性疾病弗里德赖希共济失调中缺乏。缺乏酵母铁调素同源物（Yfh1p）的酵母突变体显示线粒体中铁积累以及对氧化应激的敏感性增加，这表明铁调素在线粒体铁稳态和自由基毒性中起关键作用。Yfh1p和铁调素均以前体分子的形式合成，导入线粒体后会经历两次蛋白水解切割，产生中间形式和成熟形式。最近的一项研究发现，重组大鼠线粒体加工肽酶（MPP）可将小鼠铁调素前体切割成中间形式，但不能切割成成熟形式（Koutnikova，H.，Campuzano，V.和Koenig，M.（1998年）《人类分子遗传学》7，1485 - 1489），这表明产生成熟形式的铁调素可能需要不同的肽酶。然而，在本研究中我们表明，MPP是酵母和人类铁调素成熟的唯一负责者。MPP首先将前体切割成中间形式，随后将中间形式转化为成熟大小的蛋白质。通过这种方式，MPP可能影响铁调素的功能并间接影响线粒体铁稳态。
