Recent patient studies have shown that a fatal mitochondrial disease, multiple mitochondrial dysfunctions syndrome 1 (MMDS1) arises from two distinct genetic mutations near the active site of the essential iron-sulfur (Fe/S) protein NFU1. Symptoms of MMDS1 include impaired neurological development, lactic acidosis, failure to thrive, and ultimately death in infancy – all indicative of metabolic failure. Reduced function of target Fe/S proteins lipoic acid synthetase (LIAS) and succinate dehydrogenase (SDH) in the MMDS1 disease state suggests that multiple metabolic pathways require proper function of the native NFU1 protein through Fe/S cluster delivery and trafficking. However, the precise function of NFU1 remains unknown, and there is no available treatment for MMDS1. To investigate the molecular consequences of the disease-causing Gly208Cys and Gly189Arg substitutions, the structure and function of the derivative human NFU1 proteins were analyzed <i>in vitro</i> using a suite of biochemical techniques, and compared to the native construct. In the case of G208C NFU1, substitution initiates a global structural change, which alters the monomer-dimer equilibrium such that it is unable to receive an Fe/S cluster from physiologically-relevant sources. A similar impairment of Fe/S cluster uptake also occurs in the case of G189R NFU1. To complement study of these disease-causing derivatives, selective substitutions were made at positions 189 and 208, along with positions 210 and 213, the canonical cluster-binding residues. Analysis of these NFU1 variants have provided increased understanding into the effects of substitution on Fe/S cluster coordination and transfer, and corroborated conclusions drawn from study of the G208C and G189R derivatives.

Understanding the molecular basis of multiple mitochondrial dysfunctions syndrome 1: Impact of substitution on the structure and function of the essential iron-sulfur protein NFU1

255th National Meeting (2018)

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