Mitochondrial Complex I Core Protein Regulates cAMP Signaling via Phosphodiesterase Pde2 and NAD Homeostasis in Candida albicans

Abstract

The cyclic adenosine 3′,5′-monophosphate (cAMP)/protein kinase A (PKA) pathway of Candida albicans responds to nutrient availability to coordinate a series of cellular processes for its replication and survival. The elevation of cAMP for PKA signaling must be both transitory and tightly regulated. Otherwise, any abnormal cAMP/PKA pathway would disrupt metabolic potential and ergosterol synthesis and promote a stress response. One possible mechanism for controlling cAMP levels is direct induction of the phosphodiesterase PDE2 gene by cAMP itself. Our earlier studies have shown that most single-gene-deletion mutants of the mitochondrial electron transport chain (ETC) complex I (CI) are hypersensitive to fluconazole. To understand the fluconazole hypersensitivity observed in these mutants, we focused upon the cAMP/PKA-mediated ergosterol synthesis in CI mutants. Two groups of the ETC mutants were used in this study. Group I includes CI mutants. Group II is composed of CIII and CIV mutants; group II mutants are known to have greater respiratory loss. All mutants are not identical in cAMP/PKA-mediated ergosterol response. We found that ergosterol levels are decreased by 47.3% in the ndh51Δ (CI core subunit mutant) and by 23.5% in goa1Δ (CI regulator mutant). Both mutants exhibited a greater reduction of cAMP and excessive trehalose production compared with other mutants. Despite the normal cAMP level, ergosterol content decreased by 33.0% in the CIII mutant qce1Δ as well, thereby displaying a cAMP/PKA-independent ergosterol response. While the two CI mutants have some unique cAMP/PKA-mediated ergosterol responses, we found that the degree of cAMP reduction correlates linearly with a decrease in total nicotinamide adenine dinucleotide (NAD) levels in all mutants, particularly in the seven CI mutants. A mechanism study demonstrates that overactive PDE2 and cPDE activity must be the cause of the suppressive cAMP-mediated ergosterol response in the ndh51Δ and goa1Δ. While the purpose of this study is to understand the impact of ETC proteins on pathogenesis-associated cellular events, our results reveal the importance of Ndh51p in the regulation of the cAMP/PKA pathway through Pde2p inhibition in normal physiological environments. As a direct link between Ndh51p and Pde2p remains elusive, we suggest that Ndh51p participates in NAD homeostasis that might regulate Pde2p activity for the optimal cAMP pathway state.

The mitochondrial complex I proteins of Candida albicans moderate phagocytosis and the production of pro‐inflammatory cytokines in murine macrophages and dendritic cells

“…In contrast, deletion of Ndh51p (NADH substrate binding subunit of CI) also decreases the energy homeostasis in the host cells along with the decreased responses of a few signal transduction pathways, such as the Ras1‐cAMP‐PKA pathway. This cAMP‐PKA suppression was a noted consequence of the NDH51 deletion in C. albicans via elevation of the phosphatase Pde2 in our recent report 61 . Nevertheless, the cAMP/PKA pathway and the Mkc1 pathway have now been connected to cell wall remodeling, 68,69 which explains the glucan reduction in ndh51Δ observed in this study.…”

“…This cAMP-PKA suppression was a noted consequence of the NDH51 deletion in C. albicans via elevation of the phosphatase Pde2 in our recent report. 61 Nevertheless, the cAMP/PKA pathway and the Mkc1 pathway have now been connected to cell wall remodeling, 68,69 which explains the glucan reduction in ndh51Δ observed in this study.…”

“…13,59 Moreover, the cAMP/Pka1 pathway and the Snf1 activation have been associated with Goa1p and Nuo1p respectively. 31,61 The lower immune profile is also shown in the nuo2Δ mutant, which has a normal p-Cek1/2 response. At the transcriptional level, the gene expressions for PPM synthesis were less affected in the nuo2Δ mutant than in nuo1Δ and goa1Δ.…”

“…For example, downregulation of Cek1 at transcriptional and translational levels is only shown in goa1Δ 13,59 . Moreover, the cAMP/Pka1 pathway and the Snf1 activation have been associated with Goa1p and Nuo1p respectively 31,61 …”

Fluconazole Is Neuroprotective via Interactions with the IGF-1 Receptor

“…The neuroprotective effects exhibited by fluconazole against multiple forms of neuronal insults suggest a mechanism of action that impacts early signaling events. Fluconazole’s antifungal activities are linked to decreased levels of cAMP [ 28 ], which in C. albicans is mediated by the activation of phosphodiesterase Pde2 [ 29 ]. This enzyme catalyzes the conversion of cAMP to AMP.…”