Biology subjects

Okoye, I. C.

Publications and source records attributed to Okoye, I. C..

3 recordsLinked to original sources

bioRxiv2025

ATAD3 megadalton complex in Plasmodium falciparum is essential for mitochondrial and cellular viability

Malaria remains an urgent threat to global health as the mortality and infection rates keep rising annually and our frontline antimalarials are becoming less effective due to the emergence and spread of resistance-conferring mutations. Although the mitochondrion of P. falciparum parasites is a validated drug target, there remain many uncharacterized mitochondrial proteins. The goal of this study was to investigate the essentiality and functions of a recently identified mitochondrial protein - PF3D7_0707400. Our results show that PF3D7_0707400 is an ATAD3A ortholog that is essential to parasite survival and is present in a megadalton complex that is critical for multiple mitochondrial processes such as mitochondrial RNA stability, membrane potential, ultrastructure, and protein import. This study is the first characterization, to our knowledge, of ATAD3A in unicellular organisms. ATAD3A has been previously studied in multicellular eukaryotes and has been implicated in several childhood mitochondrial diseases. Our findings here expand our knowledge on apicomplexan mitochondrial biology and our arsenal of potential antimalarial drug targets. Author SummaryEach year, malaria is responsible for about 200 million infections and 600,000 deaths across the world. Thus, it constitutes a huge global health crisis. Increasing rates of antimalarial resistance necessitates the identification and characterization of novel parasitic proteins that can be exploited for the development of new antimalarial therapeutics. To this end, the mitochondrion of P. falciparum parasites has been studied as a validated target for effective antimalarials. However, much remains to be understood about critical mitochondrial processes and proteins that are essential for mitochondrial viability and parasite survival. Our study details the first characterization of an ATAD3 protein in a unicellular eukaryote, specifically in an apicomplexan parasite. The conservation of this protein in these deep-branching organisms highlights the importance of its biological functions, further emphasizing the significance of our study. By employing advanced molecular biology techniques, we show the presence of PfATAD3 in a giant molecular complex and its essentiality in asexual P. falciparum parasites. Conditional knockdown of PfATAD3 resulted in defects in critical mitochondrial processes such as mitochondrial RNA stability, mitochondrial membrane potential, and mitochondrial morphology. Divergence of PfATAD3 from the host allows for exploitation of this protein as a target for new antimalarials.

microbiology↗

bioRxiv2025

Dual Function of Mitochondrial Complex III in Plasmodium falciparum

Complex III of the malaria parasite mitochondrial electron transport chain (mtETC) has been validated as an attractive target for currently used antimalarials. We previously showed that the main function of mtETC in blood stage Plasmodium falciparum is to regenerate ubiquinone, which serves as an obligatory co-substrate of dihydroorotate dehydrogenase (DHOD), an essential mitochondrial enzyme for pyrimidine biosynthesis. P. falciparum can be rendered resistant to all mtETC inhibitors by provision of a bypass mediated by cytosolic yeast DHOD, a fumarate-reducing enzyme. Malaria parasite mitochondrial DNA (mtDNA) encodes only 3 proteins, each a component of mtETC. However, attempts to eliminate mtDNA in transgenic parasites expressing yDHOD have been unsuccessful, suggesting the possibility that essential function(s) other than the canonical redox reactions of the mtETC also require mtDNA maintenance. Here we have tested the hypothesis that Complex III serves the dual functions of processing imported mitochondrial proteins, as well as ubiquinone regeneration. We have generated transgenic lines that conditionally express mitochondrial processing peptidase a (MPP), which is also a component of Complex III. Using these parasites, we have determined that MPP is essential even when the need for mitochondrial electron transport is bypassed. MPP knockdown also resulted in hypersensitivity of the parasites to proguanil, a drug that synergizes with mtETC inhibitors such as atovaquone. Pulldown with MPP followed by proteomics revealed the association of multiple mitochondrially targeted proteins, in addition to all components of Complex III. These results are consistent with the suggestion that Complex III in P. falciparum serves both mtETC and protein processing functions in mitochondrial physiology.

microbiology↗

bioRxiv2019

Risk of soil-transmitted helminthiasis among agrarian communities of Kogi State, Nigeria: Evaluated in the context of The Soil-Transmitted Helminthiasis Advisory Committee recommendation 2016

Soil-transmitted helminths (STH) have remained a major threat to human especially children in developing countries including Nigeria. Interventions have always been geared towards school-aged children, neglecting preschool-aged children and occupational risk adults. The Soil-Transmitted Helminthiasis Advisory Committee (STHAC) recently suggested incorporating other at-risk groups. In the context of this recommendation, this study assessed the associated risk of STH infection among agrarian communities of Kogi State, Nigeria. A total of 310 individuals of all ages participated in the cross-sectional survey. Stool samples were analyzed using standard Kato-Katz method. A total of 106 (34.2%) individuals were infected with at least one STH. Hookworm was the most prevalent (18.1%); followed by Ascaris lumbricoides (16.8%). Worm intensity was generally light. Prevalence of infection was similar between four age groups considered (preschool, school, women of reproductive age and older at-risk group). Poor socio-economic status (SES) was a major risk for STH infection. Using a 20-assets based criteria, 68 (23.1%) and 73 (24.7%) of 295 questionnaire respondents were classified into first (poorest) and fifth (richest) wealth quintiles respectively. Risk of infection with STH was 60% significantly lower in the richest wealth quintile compared to the poorest (Prevalence Ratio (PR) = 0.4843, 95% CI = 0.2704 - 0.8678, p = 0.015). Open defecators were more likely to harbour STH than those who did not (PR = 1.7878, 95% CI = 1.2366 - 2.5846, p = 0.00201). Pit latrine and water closet toilet each approximately reduced STH infection by 50% (p < 0.05). Preventive chemotherapy for all age groups, health education and provision of basic amenities especially toilets are needed in order to achieve the goal toward the 2020 target of STH control.\n\nAuthor summarySoil-transmitted helminths (STHs) are major cause of morbidities globally, especially among children in developing countries such as Nigeria. Present World Health Organization recommended control strategy solely require preventive chemotherapy targeting preschool-aged children (PSAC) and school-aged children (SAC), and the recently included women of reproductive age (WRA). The Soil-Transmitted Helminthiasis Advisory Committee (STHAC) which is saddled with responsibility of evaluating STHs status and providing appropriate recommendations proposed that preventive chemotherapy be extended to other at-risk groups. This study evaluates this and some other recommendations of STHAC 2016 using sections of a state in Nigeria where soil-transmitted helminthiasis is endemic.\n\nFindings from this study supports recommendations for extension of preventive chemotherapy to other at-risk groups apart from PSAC and SAC. It supports WASH (water, sanitation and hygiene) as integral part of STH control. This finding emphasizes the need for health education and change in attitude which could promote tenets of WASH. And very importantly, the study emphasizes the role of poverty in the persistence of STH transmission. It is the belief of the authors that there is the need for improved socio-economic status for sustainable gains of control efforts.

epidemiology↗