NDLI: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19*

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Saha, Prasenjit Prasad Sinha, Devanjan Kumar, Praveen S. K. Srivastava, Shubhi D'silva, Patrick
Description	Author Affiliation: Saha PP ( From the Department of Biochemistry, Indian Institute of Science, Bangalore 560012, Karnataka and.); Srivastava S ( From the Department of Biochemistry, Indian Institute of Science, Bangalore 560012, Karnataka and.); Kumar S K P ( the Department of Biochemistry, Karnatak University, Dharwad 580003, Karnataka, India.); Sinha D ( From the Department of Biochemistry, Indian Institute of Science, Bangalore 560012, Karnataka and.); D'Silva P ( From the Department of Biochemistry, Indian Institute of Science, Bangalore 560012, Karnataka and patrick@biochem.iisc.ernet.in.)
Abstract	Biogenesis of the iron-sulfur (Fe-S) cluster is an indispensable process in living cells. In mammalian mitochondria, the initial step of the Fe-S cluster assembly process is assisted by the NFS1-ISD11 complex, which delivers sulfur to scaffold protein ISCU during Fe-S cluster synthesis. Although ISD11 is an essential protein, its cellular role in Fe-S cluster biogenesis is still not defined. Our study maps the important ISD11 amino acid residues belonging to putative helix 1 (Phe-40), helix 3 (Leu-63, Arg-68, Gln-69, Ile-72, Tyr-76), and C-terminal segment (Leu-81, Glu-84) are critical for in vivo Fe-S cluster biogenesis. Importantly, mutation of these conserved ISD11 residues into alanine leads to its compromised interaction with NFS1, resulting in reduced stability and enhanced aggregation of NFS1 in the mitochondria. Due to altered interaction with ISD11 mutants, the levels of NFS1 and Isu1 were significantly depleted, which affects Fe-S cluster biosynthesis, leading to reduced electron transport chain complex (ETC) activity and mitochondrial respiration. In humans, a clinically relevant ISD11 mutation (R68L) has been associated in the development of a mitochondrial genetic disorder, COXPD19. Our findings highlight that the ISD11 R68A/R68L mutation display reduced affinity to form a stable subcomplex with NFS1, and thereby fails to prevent NFS1 aggregation resulting in impairment of the Fe-S cluster biogenesis. The prime affected machinery is the ETC complex, which showed compromised redox properties, causing diminished mitochondrial respiration. Furthermore, the R68L ISD11 mutant displayed accumulation of mitochondrial iron and reactive oxygen species, leading to mitochondrial dysfunction, which correlates with the phenotype observed in COXPD19 patients.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	43
Volume Number	290
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2015-10-23
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Carbon-Sulfur Lyases Physiology Iron-Regulatory Proteins Mitochondrial Diseases Physiopathology Amino Acid Sequence Chemistry Metabolism Disease Progression HeLa Cells Iron-Sulfur Proteins Molecular Sequence Data Protein Binding Protein Stability Sequence Homology, Amino Acid Research Support, Non-U.S. Gov't Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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