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Last update 08 May 2025

ISCA2

Last update 08 May 2025

Basic Info

Synonyms

HBLD1, HESB-like domain-containing protein 1, iron-sulfur cluster assembly 2

+ [3]

Introduction

Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. May be involved in the binding of an intermediate of Fe/S cluster assembly.

Drugs associated with ISCA2

KD-061

Target

HIF-1α x HIF-2α x ISCA2

Mechanism

HIF-1α inhibitors [+2]

Active Org.

University of Utah [+1]

Originator Org.

Kuda Therapeutics, Inc. [+1]

Active Indication

Locally Advanced Clear Cell Renal Cell Carcinoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ISCA2

100 Translational Medicine associated with ISCA2

0 Patents (Medical) associated with ISCA2

Literatures (Medical) associated with ISCA2

01 Apr 2025·Journal of Biological Chemistry

Mitochondrial glutaredoxin Grx5 functions as a central hub for cellular iron-sulfur cluster assembly

Article

Author: Pain, Debkumar ; Singh, Pratibha ; Dancis, Andrew ; Pandey, Ashutosh K ; Pain, Jayashree

Iron-sulfur (Fe-S) protein biogenesis in eukaryotes is mediated by two different machineries-one in the mitochondria and another in the cytoplasm. Glutaredoxin 5 (Grx5) is a component of the mitochondrial iron-sulfur cluster machinery. Here, we define the roles of Grx5 in maintaining overall mitochondrial/cellular Fe-S protein biogenesis, utilizing mitochondria and cytoplasm isolated from Saccharomyces cerevisiae cells. We previously demonstrated that isolated wild-type (WT) mitochondria themselves can synthesize new Fe-S clusters, but isolated WT cytoplasm alone cannot do so unless it is mixed with WT mitochondria. WT mitochondria generate an intermediate, called (Fe-S)_int, that is exported to the cytoplasm and utilized for cytoplasmic Fe-S cluster assembly. We here show that mitochondria lacking endogenous Grx5 (Grx5↓) failed to synthesize Fe-S clusters for proteins within the organelle. Similarly, Grx5↓ mitochondria were unable to synthesize (Fe-S)_int, as judged by their inability to promote Fe-S cluster biosynthesis in WT cytoplasm. Most importantly, purified Grx5 precursor protein, imported into isolated Grx5↓ mitochondria, rescued these Fe-S cluster synthesis/trafficking defects. Notably, mitochondria lacking immediate downstream components of the mitochondrial iron-sulfur cluster machinery (Isa1 or Isa2) could synthesize [2Fe-2S] but not [4Fe-4S] clusters within the organelle. Isa1↓ (or Isa2↓) mitochondria could still support Fe-S cluster biosynthesis in WT cytoplasm. These results provide evidence for Grx5 serving as a central hub for Fe-S cluster intermediate trafficking within mitochondria and export to the cytoplasm. Grx5 is conserved from yeast to humans, and deficiency or mutation causes fatal human diseases. Data as presented here will be informative for human physiology.

01 Feb 2025·Plant Biotechnology Journal

Creation of high‐resistant starch rice through systematic editing of amylopectin biosynthetic genes in rs4

Article

Author: Kan, Mingxi ; Liu, Guifu ; Meng, Xiangbing ; Chen, Mingjiang ; Wu, Dianxing ; Li, Wenjia ; Jing, Yanhui ; Cheng, Qiao ; Li, Jiayang ; Guo, Hongyan ; Wang, Anqi ; Zhang, Yuxin ; Yu, Hong

SummaryResistant starch (RS) is a special kind of starch with beneficial effects on obesity, type 2 diabetes and other chronic complications. Breeding high‐RS rice varieties is considered a valuable way to improve public health. However, most rice cultivars only contain an RS level lower than 2% in cooked rice, and cloning of RS genes is critical to improve RS levels in rice. The loss of function of Starch Synthases IIIa (SSIIIa) and SSIIIb, two amylopectin biosynthetic genes, could elevate RS levels up to 10%. Here, we performed a systematic genetic study of 14 amylopectin biosynthetic genes in the ssIIIa ssIIIb double mutant via genome editing, and investigated their effects on RS formation, the eating quality and grain yield. The results showed that deficiency in SSIIa, SSIVb or ISA2 under the ssIIIa ssIIIb background could each elevate RS content to above 14%, and the quadruple mutants of sbeI sbeIIb ssIIIa ssIIIb and sbeI ssIVb ssIIIa ssIIIb could further increase RS levels to over 18%. Furthermore, the eating quality of cooked rice and grain yield decreased along with the elevated RS contents, showing a trade‐off among these traits. In these mutants, ssIIIa ssIIIb showed the balanced performance of RS and grain yield. This study provides insights into RS biosynthesis with a series of RS genes in the amylopectin biosynthesis pathway and practical strategy to breed high‐RS rice varieties with balanced performance.

01 Oct 2023·PLoS pathogens

Adaptation of the late ISC pathway in the anaerobic mitochondrial organelles of Giardia intestinalis.

Article

Author: Arbonová, Lenka ; Šuťák, Róbert ; Najdrová, Vladimíra ; Malych, Ronald ; Ettema, Thijs J G ; Motyčková, Alžběta ; Svärd, Staffan ; Janowicz, Natalia ; Stairs, Courtney W ; Benda, Martin ; Doležal, Pavel ; Voleman, Luboš ; Dohnálek, Vít

Mitochondrial metabolism is entirely dependent on the biosynthesis of the [4Fe-4S] clusters, which are part of the subunits of the respiratory chain. The mitochondrial late ISC pathway mediates the formation of these clusters from simpler [2Fe-2S] molecules and transfers them to client proteins. Here, we characterized the late ISC pathway in one of the simplest mitochondria, mitosomes, of the anaerobic protist Giardia intestinalis that lost the respiratory chain and other hallmarks of mitochondria. In addition to IscA2, Nfu1 and Grx5 we identified a novel BolA1 homologue in G. intestinalis mitosomes. It specifically interacts with Grx5 and according to the high-affinity pulldown also with other core mitosomal components. Using CRISPR/Cas9 we were able to establish full bolA1 knock out, the first cell line lacking a mitosomal protein. Despite the ISC pathway being the only metabolic role of the mitosome no significant changes in the mitosome biology could be observed as neither the number of the mitosomes or their capability to form [2Fe-2S] clusters in vitro was affected. We failed to identify natural client proteins that would require the [2Fe-2S] or [4Fe-4S] cluster within the mitosomes, with the exception of [2Fe-2S] ferredoxin, which is itself part of the ISC pathway. The overall uptake of iron into the cellular proteins remained unchanged as also observed for the grx5 knock out cell line. The pull-downs of all late ISC components were used to build the interactome of the pathway showing specific position of IscA2 due to its interaction with the outer mitosomal membrane proteins. Finally, the comparative analysis across Metamonada species suggested that the adaptation of the late ISC pathway identified in G. intestinalis occurred early in the evolution of this supergroup of eukaryotes.

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ISCA2

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