The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function

Herein we characterize a novel splice variant of PINK1 (svPINK1) that is homologous to the C-terminus regulatory domain of the protein kinase. Naturally occurring non-coding antisense provides sophisticated mechanisms for diversifying genomes and we describe a human specific non-coding antisense expressed at the PINK1 locus (naPINK1). We further demonstrate that PINK1 varies in vivo when human skeletal muscle mitochondrial content is enhanced, supporting the idea that PINK1 has a physiological role in mitochondrion. The observation of concordant regulation of svPINK1 and naPINK1 during in vivo mitochondrial biogenesis was confirmed using RNAi, where selective targeting of naPINK1 results in loss of the PINK1 splice variant in neuronal cell lines.Our data presents the first direct observation that a mammalian non-coding antisense molecule can positively influence the abundance of a cis-transcribed mRNA under physiological abundance conditions. While our analysis implies a possible human specific and dsRNA-mediated mechanism for stabilizing the expression of svPINK1, it also points to a broader genomic strategy for regulating a human disease locus and increases the complexity through which alterations in the regulation of the PINK1 locus could occur.PTEN induced putative kinase 1 gene (PINK1) is a serine-threonine kinase directly linked to a recessive form of familial parkinsonism [1-4]. A mutation at the nucleotide binding site within the kinase domain renders the protein unable to protect neuroblastoma cells from apoptosis, whereas over expression of the native peptide protects SH-SY5Y cells [1,3]. Over expressed tagged PINK1 localizes to the mitochondria [2,4], raising the possibility that PINK1 phosphorylates and regulates proteins involved in oxidative phosphorylation or the mitochondrial translocator pore [5,6], processes linked to neuronal cell death [7,8]. Indeed, PINK1 inhibits mitochondrial cytochrome c release, attenuating the general apoptosis machinery [3