An Adaptation to Low Copper in Candida albicans Involving SOD Enzymes and the Alternative Oxidase

Abstract

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.

Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense

“…CrpA mediated transport or AtfA ROI activation) were sufficient to rescue Δ aceA survival blurs the line between which fungal mechanism is most important and – similar to the intertwined contributions of copper transport and PHOX systems in host response above – reinforces the interconnectedness of both fungal responses to copper extremes. Recent studies in C. albicans show a distinct response of ROI defense mechanism towards different copper-environments during infection (Broxton and Culotta, 2016; Li et al, 2015), suggesting that a similar connection as demonstrated in A. fumigatus in this study could represent a common maneuver in other fungal pathogens.…”

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

“…1D). As previously mentioned, a major adaptation to low Cu in C. albicans involves Cu sparing whereby the major cuproprotein Sod1 is downregulated (7,9). CP can induce Mnsparing responses in Staphylococcus aureus (50,51), and we tested whether the same is true for Cu sparing in C. albicans.…”

“…By repressing SOD1, Cu is spared to maintain activity of Cu-dependent cytochrome c oxidase, essential for mitochondrial respiration. Sod1 is a major cuproenzyme of the cell, and any loss in Sod1 can be significant in terms of Cu sparing (9). Evidence for such Cu sparing is seen during fungal invasion of the kidney, when SOD1 expression declines and SOD3 increases (7,8).…”

Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens

“…Specifically, C. albicans and closely related fungi express a rare form of Mn-SOD (SOD3) that resides in the cytosol, the same location as Cu/Zn-SOD1. C. albicans will switch from expressing Cu/Zn-SOD1 to cytosolic Mn-SOD3 when Cu is low, a condition that occurs in the kidney during fungal infection 153–154 . This adaptation allows C. albicans to maintain cytosolic SOD activity even in times of Cu depletion 153–154 .…”

“…C. albicans will switch from expressing Cu/Zn-SOD1 to cytosolic Mn-SOD3 when Cu is low, a condition that occurs in the kidney during fungal infection 153–154 . This adaptation allows C. albicans to maintain cytosolic SOD activity even in times of Cu depletion 153–154 . The arthropod fungal pathogen B. bassiana also contains dual cytosolic Mn and Cu/Zn-containing SODs and, moreover, expresses a pair of mitochondrial matrix SODs that use either Mn or Fe as a cofactor.…”