Mitochondrial Phosphate–Carrier Deficiency: A Novel Disorder of Oxidative Phosphorylation

Abstract

The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP). We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life. Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts. The enzyme defect was confirmed by complementation analysis in yeast. This is the first report of patients with mitochondrial phosphate-carrier deficiency.

Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis

“…These patients are informative as only two families with variants in SLC25A3 have been previously reported, and one of our patients has two novel variants and an expanded phenotype of cardiomyopathy without skeletal myopathy nor elevated lactate (Mayr et al 2007;Mayr et al 2011). In addition, these are the first patients reported who are not of Turkish descent, which indicates a larger widespread prevalence.…”

“…Variants in MT-ATP6, a mitochondrial-encoded component of the F 1 F 0 -ATP synthase, can also cause a variety of phenotypes in the Leigh syndrome spectrum (OMIM 256000) (Pitceathly et al 2012). Recently, reports have emerged describing the first examples of pathogenic variants in the mitochondrial PiC (Mayr et al 2007;Mayr et al 2011). …”

“…Exons 3A and 3B are more than 70% identical and encode 42 and 41 amino acids, respectively. In the two previously reported Turkish families, one had a homozygous c.158-9A>G transition creating a novel splice acceptor site in intron 2 (family 1), and the other has a homozygous c.215G>A (p.G72E) transition within exon 3A (family 2) (Mayr et al 2007;Mayr et al 2011). Of the five affected children in these families, three died within the first year of life from hypertrophic cardiomyopathy and lactic acidosis (Patients 1-1, 2-1, and 2-2), and two brothers were alive at nine and seventeen years with stable hypertrophic cardiomyopathy, proximal muscle weakness, and exercise intolerance (Patients 1-2 and 1-3) ( Table 1).…”

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

“…The functional importance of the PiC was first demonstrated in yeast (S. cerevisiae) that exhibited delayed growth or failed to grow on non-fermentable substrate when deleted for MIR1, the yeast homologue of PiC [41] or for MIR1 and PIC2 [42], respectively. PIC2 encodes a second mitochondrial Pi carrier in yeast and also in Arabidopsis thaliana, shares 40% homology to mir1, and appears to play a role under certain stress conditions [43].…”

“…It is only very recently that the role of the PiC in ATP production and oxidative phosphorylation has been confirmed in mammals. This was achieved using mouse models of PiC depletion [44,45] and by studying a loss-offunction mutation in the human SLC25A3 gene [42] (see below).…”