A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation

Kumar, R.; Landry, Aaron P.; Guha, Arkajit; Vitvitsky, Victor; Lee, Ho‐Joon; Seike, Keisuke; Reddy, Pavan; Lyssiotis, Costas A.; Banerjee, Ruma

doi:10.1016/j.jbc.2021.101435

Cited by 35 publications

(35 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In other organisms living in anaerobic or microaerophilic environments (e.g., E. coli [ 41 ], Mycobacterium tuberculosis [ 32 , 42 , 43 , 44 ], Ascaris suum (adult stage) [ 29 ], Echinococcus multilocularis (protoscoleces) [ 45 ], and even in several solid tumor cells [ 46 ]), the QFR activity of complex II is well documented and has been suggested to play an important role in environmental adaptation. Previously, we demonstrated that the disruption of the Fp subunit-encoding gene of P. falciparum ( sdha ) impairs the growth of blood-stage parasites; the growth of the Δsdha mutant was rescued by succinate but not by fumarate, suggesting that this plasmodial complex II might function as a QFR rather than as a SQR [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III

et al. 2022

View full text Add to dashboard Cite

Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite’s ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC50 of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC50 = 10.26 μM) and Dd2-ELQ300 strains (EC50 = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.

show abstract

Section: Resultsmentioning

confidence: 99%

Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Among many mediators, H 2 S can induce such effects, for instance through persulfidation of protein cysteines or through its actions on metal-containing active centers [ 4 ]. For instance, in cancer cells, H 2 S has been shown to drive SQR-dependent respiration causing a reversal of the TCA cycle, glutamine deprivation, increased glycolysis and lipogenesis – effects that are not ultimately linked to altered expression of SQR protein [ 42 ]. In other cell types – e.g.…”

Section: Resultsmentioning

confidence: 99%

Role of the cystathionine β-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

Panagaki¹,

Pecze²,

Randi³

et al. 2022

Redox Biology

View full text Add to dashboard Cite

“…Physiologically, SDHA maturation is critical for the correct functioning of mature CII. As CII is a master controller of metabolism that connects the Krebs cycle 36 with bioenergetics during aerobic respiration, oxygen limitation 37 or sulfide signaling 38 , SDHA maturation has broad physiological implications.…”

Section: Discussionmentioning

confidence: 99%

Disordered-to-ordered transitions in assembly factors allow the Complex II catalytic subunit to switch binding partners

Sharma

Maklashina

Voehler

et al. 2022

Preprint

View full text Add to dashboard Cite

Mitochondrial Complex II (CII) activity supports multiple types of respiration and connects metabolic state with succinate signaling. It is therefore unsurprising that CII activity has been linked to biological phenomena that require crosstalk between metabolism and signaling, including neurodegeneration, metabolic shifts in cancer, immune activation, and ischemia reperfusion injury. In each of these processes, CII activity may be regulated at the level of assembly, with the disassembled SDHA subunit stored as metastable species with one or more assembly factors. However, both the exact molecular nature of these species and the mechanism of release of SDHA from these metastable species is unclear. In this work, we identified that transfer of SDHA into CII proceeds through at least three metastable intermediates, we assigned the sequence of appearance of these intermediates, and we determined structures for two of these. A complex between SDHA and one of its assembly factors, succinate dehydrogenase assembly factor 2 (SDHAF2), is likely the main alternative species that accumulates in cells. A second assembly factor, succinate dehydrogenase assembly factor 4 (SDHAF4), must displace SDHAF2 for assembly to proceed. Changes in intrinsic disorder in both SDHAF2 and SDHAF4 are required to release SDHA from the metastable complexes. Evaluation of unrelated biological complexes suggests that changes in disorder may guide post-folding biogenesis during both self-assembly and assisted assembly.

show abstract

A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation

Cited by 35 publications

References 57 publications

Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III

Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III

Role of the cystathionine β-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

Disordered-to-ordered transitions in assembly factors allow the Complex II catalytic subunit to switch binding partners

Contact Info

Product

Resources

About