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Mitochondria play a key role in metabolic transitions involved in the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), but the underlying molecular mechanisms remain largely unexplored. To obtain new insight into the mechanisms of cellular reprogramming, we studied the role of FAH domain-containing protein 1 (FAHD1) in the reprogramming of murine embryonic fibroblasts (MEFs) into iPSCs and their subsequent differentiation into neuronal cells. MEFs from wild type (WT) and Fahd1-knock-out (KO) mice were reprogrammed into iPSCs and characterized for alterations in metabolic parameters and the expression of marker genes indicating mitochondrial biogenesis. Fahd1-KO MEFs showed a higher reprogramming efficiency accompanied by a significant increase in glycolytic activity as compared to WT. We also observed a strong increase of mitochondrial DNA copy number and expression of biogenesis marker genes in Fahd1-KO iPSCs relative to WT. Neuronal differentiation of iPSCs was accompanied by increased expression of mitochondrial biogenesis genes in both WT and Fahd1-KO neurons with higher expression in Fahd1-KO neurons. Together these observations establish a role of FAHD1 as a potential negative regulator of reprogramming and add additional insight into mechanisms by which FAHD1 modulates mitochondrial functions.

Voltage-gated calcium channels regulate gene expression by controlling calcium entry through the plasma membrane and by direct interactions of channel fragments and auxiliary β subunits with promoters and the epigenetic machinery in the nucleus. Mutations of the calcium channel β(4) subunit gene (CACNB4) cause juvenile myoclonic epilepsy in humans and ataxia and epileptic seizures in mice. Recently a model has been proposed according to which failed nuclear translocation of the truncated β(4) subunit R482X mutation resulted in altered transcriptional regulation and consequently in neurological disease. Here we examined the nuclear targeting properties of the truncated β(4b(1–481)) subunit in tsA-201 cells, skeletal myotubes, and in hippocampal neurons. Contrary to expectation, nuclear targeting of β(4b(1–481)) was not reduced compared with full-length β(4b) in any one of the three cell systems. These findings oppose an essential role of the β(4) distal C-terminus in nuclear targeting and challenge the idea that the nuclear function of calcium channel β(4) subunits is critically involved in the etiology of epilepsy and ataxia in patients and mouse models with mutations in the CACNB4 gene.