Open AccessLeishmania type II dehydrogenase is essential for parasite viability irrespective of the presence of an active complex I
Author(s) -
Margarida Duarte,
Cleide E. Ferreira,
Gurleen Kaur Khandpur,
Tamara Flohr,
Jannik Zimmermann,
Helena Carla Castro,
J. M. Herrmann,
Bruce Morgan,
Ana M. Tomás
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2103803118
Subject(s) - leishmania , biology , leishmania infantum , nadh dehydrogenase , biochemistry , respiratory chain , nad+ kinase , mitochondrion , dehydrogenase , leishmaniasis , parasite hosting , enzyme , gene , genetics , mitochondrial dna , visceral leishmaniasis , world wide web , computer science
Type II NADH dehydrogenases (NDH2) are monotopic enzymes present in the external or internal face of the mitochondrial inner membrane that contribute to NADH/NAD+ balance by conveying electrons from NADH to ubiquinone without coupled proton translocation. Herein, we characterize the product of a gene present in all species of the human protozoan parasite Leishmania as a bona fide, matrix-oriented, type II NADH dehydrogenase. Within mitochondria, this respiratory activity concurs with that of type I NADH dehydrogenase (complex I) in some Leishmania species but not others. To query the significance of NDH2 in parasite physiology, we attempted its genetic disruption in two parasite species, exhibiting a silent ( Leishmania infantum , Li) and a fully operational ( Leishmania major , Lm) complex I. Strikingly, this analysis revealed that NDH2 abrogation is not tolerated by Leishmania , not even by complex I-expressing Lm species. Conversely, complex I is dispensable in both species, provided that NDH2 is sufficiently expressed. That a type II dehydrogenase is essential even in the presence of an active complex I places Leishmania NADH metabolism into an entirely unique perspective and suggests unexplored functions for NDH2 that span beyond its complex I-overlapping activities. Notably, by showing that the essential character of NDH2 extends to the disease-causing stage of Leishmania , we genetically validate NDH2-an enzyme without a counterpart in mammals-as a candidate target for leishmanicidal drugs.