The Emerging Role of MitomiRs in the Pathophysiology of Human Disease.

microRNAs (miRNAs) are small, single-stranded noncoding RNA molecules involved in posttranscriptional control of gene expression of a wide number of genes. miRNAs align and bind especially to 3'UTR sequences of their target genes and initiate either mRNA degradation or translational repression, resulting in reduced protein levels. miRNAs are now recognized as major players in virtually every biological process. In recent years, the discovery of miRNAs has revolutionized the traditional view of gene expression and our understanding of miRNA biogenesis and function has thereby expanded. The discovery of mitochondrial-located miRNAs raises the issue of the molecular mechanism underlying their translocation from the nucleus to the mitochondria. Studies in different species indicate that it may exist a number of import pathways of nucleus-encoded RNAs to mitochondria, being the most of them largely ATP-dependent. Not only pre-miRNAs, but also mature miRNAs, are present in the mitochondria; these findings have also raised the possibility of mitochondrial miRNA synthesis. Some pre-miRNAs sequences seem to be processed in the mitochondria, giving origin to mature miRNAs, which could be immediately active on the mitochondrial transcripts or exported to the cytosol in order to interfere with genomic-derived mRNA. Thus, the mitochondrial-processed miRNAs are likely to contribute to some posttranscriptional regulation of gene expression related to the mitochondrial functions. Coming from their location, the mitochondria, some miRNAs are currently named as mitomiRs; it refers to those miRNAs that can localize in mitochondria, whether transcribed from the nuclear or, potentially, the mitochondrial genome. When their genomics was analyzed, a number of mitomiRs mapped the nuclear genome at loci relevant to mitochondrial functions or diseases. Current computational analyses, using different algorithms, drive scientists to argue that the mitochondrial genome can harbor sequences that could be a target for several mitomiRs. However, perhaps a more challenging topic concerning mitomiRs is whether the mitochondrial DNA can harbor miRNA sequences, indicating an involvement of mitochondria in small RNA-generating pathways. The identification of populations of miRNAs in the mitochondria pushed scientists in the field to question its biological functions. It is established that miRNAs, originated in the nuclear genome, are exported to cytosol where they are processed and exert their function by inhibiting nuclear genome-derived mRNA. Actually it is also known that some miRNAs are imported into mitochondria where they interact with some mitochondrial genome-derived mRNA molecules. More strikingly, it has also come to light that mitochondrial genome (mtDNA) can originate some miRNA molecules that exert their function directly on mitochondrial transcripts. The links between miRNA deregulation and human disease have been reported in almost all medicine fields. Currently, great efforts are being invested in understanding the involvement of miRNA deregulation in disease and unlocking the mechanisms by which they act. This new field of investigation has revealed the tremendous potential of miRNAs as diagnostic or even as valuable therapeutic tools. miRNAs have recently emerged as key regulators of metabolism. Metabolic syndrome is a systemic disorder that includes a spectrum of abnormalities associated with obesity and type II diabetes. Defects in mitochondrial function, namely related to oxidation of fatty acids, have been linked to diet-induced obesity and the development of insulin resistance in adipose tissue and skeletal muscle. Consistently, obese individuals have mitochondria with compromised bioenergetic capacity. Therefore, increasing interest is being given to the role of miRNAs on metabolic regulation, with relevance on mitochondria and the mechanisms purported for miRNA actions, particularly acting in mitochondria or in mitochondria-related pathways. The involvement of miRNAs in mitochondrial metabolism, mitochondrial oxidative phosphorylation (OXPHOS), electron transport chain (ETC) components, lipid metabolism, and metabolic disorders is becoming more and more comprehended, as well as miRNAs contribution for processes such as mitochondrial dynamics or apoptosis regulation and cancer.