A microRNA’s journey to the center of the mitochondria

Abstract

MicroRNAs (miRNAs) are known as the master regulators of gene expression, and for the last two decades our knowledge of their functional reach keeps expanding. Recent studies have shown that a miRNA's role in regulation extends to extracellular and intracellular organelles. Several studies have shown a role for miRNA in regulating the mitochondrial genome in normal and disease conditions. Mitochondrial dysfunction occurs in many human pathologies, such as cardiovascular disease, diabetes, cancer, and neurological diseases. These studies have shed some light on regulation of the mitochondrial genome as well as helped to explain the role of miRNA in altering mitochondrial function and the ensuing effects on cells. Although the field has grown in recent years, many questions still remain. For example, little is known about how nuclear-encoded miRNAs translocate to the mitochondrial matrix. Knowledge of the mechanisms of miRNA transport into the mitochondrial matrix is likely to provide important insights into our understanding of disease pathophysiology and could represent new targets for therapeutic intervention. For this review, our focus will be on the role of a subset of miRNAs, known as MitomiR, in mitochondrial function. We also discuss the potential mechanisms used by these nuclear-encoded miRNAs for import into the mitochondrial compartment. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/microrna-translocation-into-the-mitochondria/ .

Mitochondrial regulation in skeletal muscle: A role for non‐coding RNAs?

“…However, further studies are required to examine the extent to which pre‐miRs also undergo processing within the mitochondria. Potential transport mechanisms of mature and immature miRNAs into the mitochondria are discussed in other reviews (Bandiera et al., ; Borralho, Rodrigues, & Steer, ; Duarte, Palmeira, & Rolo, ; Macgregor‐Das & Das, ; Sripada, Tomar & Singh, ) and suggest a role for AGO2 (Maniataki & Mourelatos, ), polynucleotide phosphorylase (PNPASE; Shepherd et al., ; G. Wang et al., ), P‐bodies (Huang et al., ) and voltage‐gated ion channels (Salinas et al., ).…”

“…transport mechanisms of mature and immature miRNAs into the mitochondria are discussed in other reviews(Bandiera et al, 2013;Borralho, Rodrigues, & Steer, 2015;Duarte, Palmeira, & Rolo, 2014;Macgregor-Das & Das, 2018; and suggest a role for AGO2(Maniataki & Mourelatos, 2005), polynucleotide phosphorylase (PNPASE;Shepherd et al, 2017;G. Wang et al, 2010), P-bodies(Huang et al, 2011) and voltage-gated ion channels(Salinas et al, 2006).The presence of AGO2 and dicer in the mitochondria, along with immature forms of miRNAs, reinforces the idea that some level of miRNA-mediated post-transcriptional regulation occurs in TA B L E 1 Skeletal muscle-related mitochondrial microRNAs mitochondrial miRNAs were classified as canonical myomiRs, skeletal muscle-enriched miRNAs and cardiac muscle-enriched miRNAs.…”

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…In proliferating cells, genes with shorter 3′‐UTR can omit their miRNA target sites, resulting in higher protein expression. Finally, miRNAs can be sequestered by mRNAs, lncRNAs, and circRNAs that contain miRNA binding sites and thus acting as a sponge . Argonaute (Ago) protein is an RNA‐binding protein, which exists in the extracellular space as a free protein or in secreted exosomes along with other RNA‐processing proteins.…”

“…Finally, miRNAs can be sequestered by mRNAs, lncRNAs, and circRNAs that contain miRNA binding sites and thus acting as a sponge. [65][66][67][68] Argonaute (Ago) protein is an RNAbinding protein, which exists in the extracellular space as a free protein or in secreted exosomes along with other RNAprocessing proteins. Ago accumulates in cytoplasmic processing bodies (P-bodies), where additional binding interactions promote mRNA decay and translational inhibition.…”

The Influence of MicroRNAs on Mitochondrial Calcium

“…The subset of miRNAs, which translocate into the mitochondria and are functionally active, i.e., RNA-induced silencing complex, or RISC, is inside the mitochondrial compartment, are termed mitochondrial miRNA or MitomiR. The mitochondrial miRNA translocation phenomenon has not been extensively studied (Macgregor-Das and Das, 2018 ), but MitomiRs can influence various mitochondrial functions, such as the TCA, ETC, lipid metabolism, and amino acid metabolism (Baradan et al, 2017 ). It has been demonstrated that MitomiRs can post-translationally regulate gene function inside the mitochondrial fraction either by targeting a nuclear-encoded gene present in the mitochondria or by targeting a mitochondrial encoded-gene (Das et al, 2012 , 2014 , 2017 ).…”