Molekulární funkce AFG2A (SPATA5) u vzácné genetické neurovývojové poruchy a cesta k terapii

Faltínová, Pavlína

The ATPase family gene 2 protein homolog A (AFG2A) is a gene located on the long arm of chromosome 4, which codes for a protein of the same name belonging to the adenosine triphosphatases associated with diverse cellular activities (AAA+ ATPase) family. It plays a role in maintaining mitochondrial integrity, recycling replisome proteins, ensuring the smooth progression of the replication fork, and in the late maturation steps of the pre-60S ribosomal subunit. Furthermore, variants in the AFG2A gene are associated with a rare neurodegenerative disease with autosomal recessive inheritance known as Neurodevelopmental disorder with hearing loss, seizures and brain abnormalities (NEDHSB) with no efficient causative therapy currently available. Here, we present a human embryonic kidney (HEK) 293 cell AFG2A knockdown model (hereafter referred to as HEK 293 AFG2A KD), which we subjected to a series of functional analyses to better understand the protein's biological activity. First, we observed that AFG2A deficiency results in a quantitative depletion of mitochondria with intact membrane potential, as well as a significant decrease in their volume and surface area. Furthermore, we noticed attenuated basal and ATP-dependent oxygen consumption rates (OCRs) accompanied by an apparent but non-significant...

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