Broxton Chynna N, Culotta Valeria C
Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States of America.
PLoS One. 2016 Dec 29;11(12):e0168400. doi: 10.1371/journal.pone.0168400. eCollection 2016.
In eukaryotes, the Cu/Zn superoxide dismutase (SOD1) is a major cytosolic cuproprotein with a small fraction residing in the mitochondrial intermembrane space (IMS) to protect against respiratory superoxide. Curiously, the opportunistic human fungal pathogen Candida albicans is predicted to express two cytosolic SODs including Cu/Zn containing SOD1 and manganese containing SOD3. As part of a copper starvation response, C. albicans represses SOD1 and induces the non-copper alternative SOD3. While both SOD1 and SOD3 are predicted to exist in the same cytosolic compartment, their potential role in mitochondrial oxidative stress had yet to be investigated. We show here that under copper replete conditions, a fraction of the Cu/Zn containing SOD1 localizes to the mitochondrial IMS to guard against mitochondrial superoxide. However in copper starved cells, localization of the manganese containing SOD3 is restricted to the cytosol leaving the mitochondrial IMS devoid of SOD. We observe that during copper starvation, an alternative oxidase (AOX) form of respiration is induced that is not coupled to ATP synthesis but maintains mitochondrial superoxide at low levels even in the absence of IMS SOD. Surprisingly, the copper-dependent cytochrome c oxidase (COX) form of respiration remains high with copper starvation. We provide evidence that repression of SOD1 during copper limitation serves to spare copper for COX and maintain COX respiration. Overall, the complex copper starvation response of C. albicans involving SOD1, SOD3 and AOX minimizes mitochondrial oxidative damage whilst maximizing COX respiration essential for fungal pathogenesis.
在真核生物中，铜锌超氧化物歧化酶（SOD1）是一种主要的胞质铜蛋白，有一小部分存在于线粒体外膜间隙（IMS）中，以抵御呼吸作用产生的超氧化物。奇怪的是，推测机会性人类真菌病原体白色念珠菌会表达两种胞质超氧化物歧化酶，包括含铜锌的SOD1和含锰的SOD3。作为铜饥饿反应的一部分，白色念珠菌会抑制SOD1并诱导非铜替代物SOD3。虽然预计SOD1和SOD3都存在于同一胞质区室中，但它们在线粒体氧化应激中的潜在作用尚未得到研究。我们在此表明，在铜充足的条件下，一部分含铜锌的SOD1定位于线粒体外膜间隙，以抵御线粒体超氧化物。然而，在铜饥饿的细胞中，含锰的SOD3的定位仅限于胞质，使得线粒体外膜间隙缺乏超氧化物歧化酶。我们观察到，在铜饥饿期间，会诱导一种替代氧化酶（AOX）形式的呼吸作用，这种呼吸作用不与ATP合成偶联，但即使在没有线粒体外膜间隙超氧化物歧化酶的情况下，也能将线粒体超氧化物维持在低水平。令人惊讶的是，铜依赖性细胞色素c氧化酶（COX）形式的呼吸作用在铜饥饿时仍然很高。我们提供的证据表明，在铜限制期间抑制SOD1有助于节省铜用于COX，并维持COX呼吸作用。总体而言，白色念珠菌涉及SOD1、SOD3和AOX的复杂铜饥饿反应可将线粒体氧化损伤降至最低，同时最大限度地提高对真菌致病至关重要的COX呼吸作用。
