Mitochondrial miRNAs Research Articles

Mitochondrial-related microRNAs and their roles in cellular senescence.

Aging is a natural aspect of mammalian life. Although cellular mortality is inevitable, various diseases can hasten the aging process, resulting in abnormal or premature senescence. As cells age, they experience distinctive morphological and biochemical shifts, compromising their functions. Research has illuminated that cellular senescence coincides with significant alterations in the microRNA (miRNA) expression profile. Notably, a subset of aging-associated miRNAs, originally encoded by nuclear DNA, relocate to mitochondria, manifesting a mitochondria-specific presence. Additionally, mitochondria themselves house miRNAs encoded by mitochondrial DNA (mtDNA). These mitochondria-residing miRNAs, collectively referred to as mitochondrial miRNAs (mitomiRs), have been shown to influence mtDNA transcription and protein synthesis, thereby impacting mitochondrial functionality and cellular behavior. Recent studies suggest that mitomiRs serve as critical sensors for cellular senescence, exerting control over mitochondrial homeostasis and influencing metabolic reprogramming, redox equilibrium, apoptosis, mitophagy, and calcium homeostasis-all processes intimately connected to senescence. This review synthesizes current findings on mitomiRs, their mitochondrial targets, and functions, while also exploring their involvement in cellular aging. Our goal is to shed light on the potential molecular mechanisms by which mitomiRs contribute to the aging process.

A landscape of mouse mitochondrial small non-coding RNAs.

Small non-coding RNAs (ncRNAs), particularly miRNAs, play key roles in a plethora of biological processes both in health and disease. Although largely operative in the cytoplasm, emerging data indicate their shuttling in different subcellular compartments. Given the central role of mitochondria in cellular homeostasis, here we systematically profiled their small ncRNAs content across mouse tissues that largely rely on mitochondria functioning. The ubiquitous presence of piRNAs in mitochondria (mitopiRNA) of somatic tissues is reported for the first time, supporting the idea of a strong and general connection between mitochondria biology and piRNA pathways. Then, we found groups of tissue-shared and tissue-specific mitochondrial miRNAs (mitomiRs), potentially related to the "basic" or "cell context dependent" biology of mitochondria. Overall, this large data platform will be useful to deepen the knowledge about small ncRNAs processing and their governed regulatory networks contributing to mitochondria functions.

MicroRNAs in Syrista parreyssi (Hymenoptera) and Lepismasaccharina (Zygentoma) possibly involved in the mitochondrial function.

Mitochondria are essential organelles for maintaining vital cellular functions, and microRNAs(miRNAs) regulate gene expression posttranscriptionally. miRNAs exhibit tissue and time-specific patterns in mitochondria and specifically mitochondrial miRNAs (mitomiRs) can regulate the mRNA expression both originating from mitochondrial and nuclear transcription which affect mitochondrial metabolic activity and cell homeostasis. In this study, miRNAs of two insect species, Syrista parreyssi (Hymenoptera) and Lepisma saccharina (Zygentoma), were investigated for the first time. The known and possible novel miRNAs were predicted and characterized and their potential effects on mitochondrial transcription were investigated in these insect species using deep sequencing. The previously reported mitomiRs were also investigated and housekeeping miRNAs were characterized. miRNAs that are involved in mitochondrial processes such as apoptosis and signaling and that affect genes encoding the subunits of OXPHOS complexes have been identified in each species. Here, 81 and 161 novel mature miRNA candidates were bioinformatically predicted and 9 and 24 of those were aligned with reference mitogenomes of S. parreyssi and L. saccharina, respectively. As a result of RNAHybrid analysis, 51 and 69 potential targets of miRNAs were found in the mitogenome of S. parreyssi and L. saccharina, respectively. cox1 gene was the most targeted gene and cytB, rrnS, and rrnL genes were highly targeted in both of the species by novel miRNAs, hypothetically. We speculate that these novel miRNAs, originating from or targeting mitochondria, influence on rRNA genes or positively selected mitochondrial protein-coding genes. These findings may provide a new perspective in evaluating miRNAs for maintaining mitochondrial function and transcription.

Simultaneous Imaging of Multiple miRNAs in Mitochondria Controlled by Fluorescently Encoded Upconversion Optical Switches for Drug Resistance Studies.

Mitochondrial miRNAs (mitomiRs) are essential regulators of biological processes by influencing mitochondrial gene expression and function. To comprehensively understand related pathological processes and treatments, simultaneous imaging of multiple mitomiRs is crucial. In this study, we present a technique that enables simultaneous monitoring of multiple mitomiRs in living cells using a near-infrared (NIR) photoactivated controlled detection probe (PD-mFleU) with a fluorescence-encoded error correction module and a nonsupervised machine learning data-processing algorithm. This method allows controlled sensing imaging of mitomiRs with a DNA reporter probe that can be activated by NIR light after targeted mitochondrial localization. Multilayer upconversion nanoparticles (UCNPs) are used for encoding probes and error correction. Additionally, the density-based spatial clustering of applications with the noise (DBSCAN) algorithm is used to process and analyze the image. Using this technique, we achieved rapid in situ imaging of the abnormal expression of three mitomiRs (miR-149, miR-590, and miR-671) related to mt-ND1 in drug-resistant cells. Furthermore, upregulating the three mitomiRs simultaneously efficiently reverted drug-resistant cells to sensitive cells. Our study provides an analytical strategy for multiplex imaging of mitomiRs in living cells with potential clinical applications.

Understanding the roles and regulation of mitochondrial microRNAs (MitomiRs) in neurodegenerative diseases: Current status and advances

MicroRNAs (miRNA) are a class of small non-coding RNA, roughly 21–22 nucleotides in length, which are master gene regulators. These miRNAs bind to the mRNA's 3’ - untranslated region and regulate post-transcriptional gene regulation, thereby influencing various physiological and cellular processes. Another class of miRNAs known as mitochondrial miRNA (MitomiRs) has been found to either originate from the mitochondrial genome or be translocated directly into the mitochondria. Although the role of nuclear DNA encoded miRNA in the progression of various neurological diseases such as Parkinson's disease, Alzheimer’s disease, Huntington's disease, etc. is well known, accumulating evidence suggests the possible role of deregulated mitomiRs in the progression of various neurodegenerative diseases with unknown mechanism. We have attempted to outline the current state of mitomiRs role in controlling mitochondrial gene expression and function through this review, paying particular attention to their contribution to neurological processes, their etiology, and their potential therapeutic use.

MiRNAs activate mitochondrial energy metabolism: a narrative view

MicroRNAs (miRNAs) are small, non-coding single-stranded RNA molecules that participate in the repression of translation or degradation of messenger RNA. miRNAs play a significant role in cellular regulatory mechanisms and have been implicated in numerous pathological processes. However, research indicates the presence of miRNAs in mitochondria called mitomiRs originating from mitochondrial DNA, with direct action on genes encoding proteins and enzymes that participate in mitochondrial function. The mitochondrial localization of miRNAs has gained relevance since it was observed that mitomiR populations are modified throughout the cell cycle. Currently, miRNAs are known to act in several biological processes, including being considered key to better understand several processes that lead to ATP production as well as mitochondrial dysfunctions. Thus, the objective of this review is to narrate the molecular mechanisms of miRNAs actions in mitochondrial energy pathway.

Altered trafficking of miRNAs at mitochondria modulates mitochondrial functions and cell death in brain ischemia.

Stroke is one of the major causes of death and disabilities worldwide. The rapid induction of cell death by necrosis and apoptosis is observed at the ischemic core, while long lasting apoptosis and brain inflammation continue in the penumbra. The emerging evidence suggests a critical role of mitochondria in acute and chronic inflammation and cell death. Mitochondrial dysfunction may result in the release of mitokines and/or mitochondrial DNA into the cytoplasm and activate multiple cytosolic pathways which in turn triggers inflammation. The role of miRNA, specifically mitochondria-associated miRNAs (mitomiRs) in the regulation of mitochondrial functions is emerging. In the current study, we hypothesized that ischemia-induced mitomiRs may modulate the mitochondrial functions and such alterations under stress conditions may lead to mitochondrial dysfunction and cell death. We have demonstrated the specific pattern of miRNAs associated with mitochondria that is altered under ischemic condition induced by transient middle artery occlusion (tMCAo) in rats. The putative targets of altered miRNAs include several mitochondrial proteins which signifies their involvement in maintaining mitochondrial homeostasis. The alterations of selected miRNA in mitochondria was further detected in a cellular models when hypoxia is induced using a chemical agent CoCl2 in three cell lines. Two candidate mitomiRs, hsa-miR-149-3p and hsa-miR-204-5p were further analyzed for their functional role during in vitro hypoxia by transfecting mitomiR mimics into cells and determining critical mitochondrial functions and cell viability. The results here emphasize the role of certain mitomiRs as an important modulator of mitochondrial function under the ischemic condition.

Mitochondria Localized microRNAs: An Unexplored miRNA Niche in Alzheimer's Disease and Aging.

Mitochondria play several vital roles in the brain cells, especially in neurons to provide synaptic energy (ATP), Ca2+ homeostasis, Reactive Oxygen Species (ROS) production, apoptosis, mitophagy, axonal transport and neurotransmission. Mitochondrial dysfunction is a well-established phenomenon in the pathophysiology of many neurological diseases, including Alzheimer's disease (AD). Amyloid-beta (Aβ) and Phosphorylated tau (p-tau) proteins cause the severe mitochondrial defects in AD. A newly discovered cellular niche of microRNAs (miRNAs), so-called mitochondrial-miRNAs (mito-miRs), has recently been explored in mitochondrial functions, cellular processes and in a few human diseases. The mitochondria localized miRNAs regulate local mitochondrial genes expression and are significantly involved in the modulation of mitochondrial proteins, and thereby in controlling mitochondrial function. Thus, mitochondrial miRNAs are crucial to maintaining mitochondrial integrity and for normal mitochondrial homeostasis. Mitochondrial dysfunction is well established in AD pathogenesis, but unfortunately mitochondria miRNAs and their precise roles have not yet been investigated in AD. Therefore, an urgent need exists to examine and decipher the critical roles of mitochondrial miRNAs in AD and in the aging process. The current perspective sheds light on the latest insights and future research directions on investigating the contribution of mitochondrial miRNAs in AD and aging.

MiRNAs Action and Impact on Mitochondria Function, Metabolic Reprogramming and Chemoresistance of Cancer Cells: A Systematic Review

MicroRNAs (miRNAs) are involved in the regulation of mitochondrial function and homeostasis, and in the modulation of cell metabolism, by targeting known oncogenes and tumor suppressor genes of metabolic-related signaling pathways involved in the hallmarks of cancer. This systematic review focuses on articles describing the role, association, and/or involvement of miRNAs in regulating the mitochondrial function and metabolic reprogramming of cancer cells. Following the PRISMA guidelines, the articles reviewed were published from January 2010 to September 2022, with the search terms "mitochondrial microRNA" and its synonyms (mitochondrial microRNA, mitochondrial miRNA, mito microRNA, or mitomiR), "reprogramming metabolism," and "cancer" in the title or abstract). Thirty-six original research articles were selected, revealing 51 miRNAs with altered expression in 12 cancers: bladder, breast, cervical, colon, colorectal, liver, lung, melanoma, osteosarcoma, pancreatic, prostate, and tongue. The actions of miRNAs and their corresponding target genes have been reported mainly in cell metabolic processes, mitochondrial dynamics, mitophagy, apoptosis, redox signaling, and resistance to chemotherapeutic agents. Altogether, these studies support the role of miRNAs in the metabolic reprogramming hallmark of cancer cells and highlight their potential as predictive molecular markers of treatment response and/or targets that can be used for therapeutic intervention.

The context signals of mitochondrial miRNAs (mitomiRs) of mammals.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level in the cytoplasm and play an important role in a wide range of biological processes. Recent studies have found that the miRNA sequences are presented not only in the cytoplasm, but also in the mitochondria. These miRNAs (the so-called mitomiRs) may be the sequences of nuclear or mitochondrial origin; some of them are involved in regulation of the mitochondrial gene functions, while the role of others is still unknown. The identification of nucleotide signals, which are unique to mitomiRs, may help to determine this role. We formed a dataset that combined the experimentally discovered mitomiRs in human, rat and mouse. To isolate signals that may be responsible for the mitomiRs' functions or for their translocation from or into mitochondria a context analysis was carried out for the sequences. For three species in the group mitomiRs/non-mitomiRs and the group of all miRNAs from the miRBase database statistically overrepresented 8-letter motifs were identified (p-value < 0.01 with Bonferroni correction for multiple comparisons), for these motifs the patterns of the localization in functionally important regions for different types of miRNAs were found. Also, for the group mitomiRs/non-mitomiRs we found the statistically significant features of the miRNA nucleotide context near the Dicer and Drosha cleavage sites (Pearson's χ2 test of independence for the first three positions of the miRNA, p-value < 0.05). The observed nucleotide frequencies may indicate a more homogeneous pri-miRNA cleavage by the Drosha complex during the formation of the 5' end of mitomiRs. The obtained results can help to determine the role of the nucleotide signals in the origin, processing, and functions of the mitomiRs.

The Role of Mitochondrial miRNAs in the Development of Radon-Induced Lung Cancer.

MicroRNAs are short, non-coding RNA molecules regulating gene expression by inhibiting the translation of messenger RNA (mRNA) or leading to degradation. The miRNAs are encoded in the nuclear genome and exported to the cytosol. However, miRNAs have been found in mitochondria and are probably derived from mitochondrial DNA. These miRNAs are able to directly regulate mitochondrial genes and mitochondrial activity. Mitochondrial dysfunction is the cause of many diseases, including cancer. In this review, we consider the role of mitochondrial miRNAs in the pathogenesis of lung cancer with particular reference to radon exposure.

Mitochondrial MicroRNAs Contribute to Macrophage Immune Functions Including Differentiation, Polarization, and Activation.

A subset of microRNA (miRNA) has been shown to play an important role in mitochondrial (mt) functions and are named MitomiR. They are present within or associated with mitochondria. Most of the mitochondrial miRNAs originate from the nucleus, while a very limited number is encoded by mtDNA. Moreover, the miRNA machinery including the Dicer and Argonaute has also been detected within mitochondria. Recent, literature has established a close relationship between miRNAs and inflammation. Indeed, specific miRNA signatures are associated with macrophage differentiation, polarization and functions. Nevertheless, the regulation of macrophage inflammatory pathways governed specifically by MitomiR and their implication in immune-mediated inflammatory disorders remain poorly studied. Here, we propose a hypothesis in which MitomiR play a key role in triggering macrophage differentiation and modulating their downstream activation and immune functions. We sustain this proposition by bioinformatic data obtained from either the human monocytic THP1 cell line or the purified mitochondrial fraction of PMA-induced human macrophages. Interestingly, 22% of the 754 assayed miRNAs were detected in the mitochondrial fraction and are either exclusively or highly enriched cellular miRNA. Furthermore, the in silico analysis performed in this study, identified a specific MitomiR signature associated with macrophage differentiation that was correlated with gene targets within the mitochondria genome or with mitochondrial pathways. Overall, our hypothesis and data suggest a previously unrecognized link between MitomiR and macrophage function and fate. We also suggest that the MitomiR-dependent control could be further enhanced through the transfer of mitochondria from donor to target cells, as a new strategy for MitomiR delivery.

MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence.

Mitochondria are essential organelles that generate most of the chemical energy to power the cell through ATP production, thus regulating cell homeostasis. Although mitochondria have their own independent genome, most of the mitochondrial proteins are encoded by nuclear genes. An extensive bidirectional communication network between mitochondria and the nucleus has been discovered, thus making them semi-autonomous organelles. The nucleus-to-mitochondria signaling pathway, called Anterograde Signaling Pathway can be deduced, since the majority of mitochondrial proteins are encoded in the nucleus, less is known about the opposite pathway, the so-called mitochondria-to-nucleus retrograde signaling pathway. Several studies have demonstrated that non-coding RNAs are essential “messengers” of this communication between the nucleus and the mitochondria and that they might have a central role in the coordination of important mitochondrial biological processes. In particular, the finding of numerous miRNAs in mitochondria, also known as mitomiRs, enabled insights into their role in mitochondrial gene transcription. MitomiRs could act as important mediators of this complex crosstalk between the nucleus and the mitochondria. Mitochondrial homeostasis is critical for the physiological processes of the cell. Disruption at any stage in their metabolism, dynamics and bioenergetics could lead to the production of considerable amounts of reactive oxygen species and increased mitochondrial permeability, which are among the hallmarks of cellular senescence. Extensive changes in mitomiR expression and distribution have been demonstrated in senescent cells, those could possibly lead to an alteration in mitochondrial homeostasis. Here, we discuss the emerging putative roles of mitomiRs in the bidirectional communication pathways between mitochondria and the nucleus, with a focus on the senescence-associated mitomiRs.

Spatially Selective Imaging of Mitochondrial MicroRNAs via Optically Programmable Strand Displacement Reactions

AbstractMicroRNA (miRNA) functions are tightly regulated by their sub‐compartmental location in living cells, and the ability to imaging of mitochondrial miRNAs (mitomiRs) is essential for understanding of the related pathological processes. However, most existing DNA‐based methods could not be used for this purpose. Here, we report the development of a DNA nanoreporter technology for imaging of mitomiRs in living cells through near‐infrared (NIR) light‐controlled DNA strand displacement reactions. The sensing function of the DNA nanoreporters are silent (OFF) during the delivery process, but can be photoactivated (ON) with NIR light after targeted mitochondrial localization, enabling spatially‐restricted imaging of two types of cancer‐related mitomiRs with improved detection accuracy. Furthermore, we demonstrate imaging of mitomiRs in vivo through spatiotemporally‐controlled delivery and activation. Therefore, this study illustrates a simple methodology that may be broadly applicable for investigating the mitomiRs‐associated physiological events.

Spatially Selective Imaging of Mitochondrial MicroRNAs via Optically Programmable Strand Displacement Reactions.

MicroRNA (miRNA) functions are tightly regulated by their sub-compartmental location in living cells, and the ability to imaging of mitochondrial miRNAs (mitomiRs) is essential for understanding of the related pathological processes. However, most existing DNA-based methods could not be used for this purpose. Here, we report the development of a DNA nanoreporter technology for imaging of mitomiRs in living cells through near-infrared (NIR) light-controlled DNA strand displacement reactions. The sensing function of the DNA nanoreporters are silent (OFF) during the delivery process, but can be photoactivated (ON) with NIR light after targeted mitochondrial localization, enabling spatially-restricted imaging of two types of cancer-related mitomiRs with improved detection accuracy. Furthermore, we demonstrate imaging of mitomiRs in vivo through spatiotemporally-controlled delivery and activation. Therefore, this study illustrates a simple methodology that may be broadly applicable for investigating the mitomiRs-associated physiological events.

TSH attenuates fatty acid oxidation in hepatocytes by reducing the mitochondrial distribution of miR-449a/449b-5p/5194

The elevated thyroid-stimulating hormone (TSH) levels contribute to the abnormal expression/activity of several key hepatic lipid metabolism enzymes. Although miRNAs have been shown to play key roles in hepatic lipid metabolism and are found in isolated mitochondria, very little is known about the pathological and physiological significance of their mitochondrial distributions in regulating liver lipid metabolism. Here, we found that TSH significantly reduced the distribution of some miRNAs in mitochondria of hepatocytes, especially miR-449a, miR-449b-5p, and miR-5194. These three miRNAs inhibited their target genes PGC1B, ABCD1, ADIPOR1 and the downstream molecule PPARA. These effects synergistically suppressed fatty acid (FA) β-oxidation in mitochondria and peroxisomes and decreased the translocation of cytosolic very long chain fatty acids to peroxisomes, which noticeably reduced FA catabolism and promoted triglyceride accumulation in hepatocytes. This study reveals the functional significance of changed miRNA mitochondrial-cytoplasmic distribution in the regulation of hepatic lipid metabolism.

Mitochondrial Dysfunction and Mitophagy Closely Cooperate in Neurological Deficits Associated with Alzheimer's Disease and Type 2 Diabetes.

Alzheimer's disease (AD) and type 2 diabetes (T2D) are known to be correlated in terms of their epidemiology, histopathology, and molecular and biochemical characteristics. The prevalence of T2D leading to AD is approximately 50-70%. Moreover, AD is often considered type III diabetes because of the common risk factors. Uncontrolled T2D may affect the brain, leading to memory and learning deficits in patients. In addition, metabolic disorders and impaired oxidative phosphorylation in AD and T2D patients suggest that mitochondrial dysfunction is involved in both diseases. The dysregulation of pathways involved in maintaining mitochondrial dynamics, biogenesis and mitophagy are responsible for exacerbating the impact of hyperglycemia on the brain and neurodegeneration under T2D conditions. The first section of this review describes the recent views on mitochondrial dysfunction that connect these two disease conditions, as the pathways are observed to overlap. The second section of the review highlights the importance of different mitochondrial miRNAs (mitomiRs) involved in the regulation of mitochondrial dynamics and their association with the pathogenesis of T2D and AD. Therefore, targeting mitochondrial biogenesis and mitophagy pathways, along with the use of mitomiRs, could be a potent therapeutic strategy for T2D-related AD. The last section of the review highlights the known drugs targeting mitochondrial function for the treatment of both disease conditions.

Expression of expanded FMR1-CGG repeats alters mitochondrial miRNAs and modulates mitochondrial functions and cell death in cellular model of FXTAS

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by an expansion of 55 to 200 CGG repeats located within 5′UTR of FMR1.These CGG repeats are transcribed into RNAs, which sequester several RNA binding proteins and alter the processing of miRNAs. CGG repeats are also translated into a toxic polyglycine-containing protein, FMRpolyG, that affects mitochondrial and nuclear functions reported in cell and animal models and patient studies. Nuclear-encoded small non-coding RNAs, including miRNAs, are transported to mitochondria; however, the role of mitochondrial miRNAs in FXTAS pathogenesis is not understood. Here, we analyzed mitochondrial miRNAs from HEK293 cells expressing expanded CGG repeats and their implication in the regulation of mitochondrial functions. The analysis of next generation sequencing (NGS) data of small RNAs from HEK293 cells expressing CGG premutation showed decreased level of cellular miRNAs and an altered pattern of association of miRNAs with mitochondria (mito-miRs). Among such mito-miRs, miR-320a was highly enriched in mitoplast and RNA immunoprecipitation of Ago2 (Argonaute-2) followed by Droplet digital PCR (ddPCR)suggested that miR-320a may form a complex with Ago2 and mitotranscripts. Finally, transfection of miR-320a mimic in cells expressing CGG permutation recovers mitochondrial functions and rescues cell death. Overall, this work reveals an altered translocation of miRNAs to mitochondria and the role of miR-320a in FXTAS pathology.

Mitochondrial microRNAs: A Putative Role in Tissue Regeneration.

Simple SummaryDistinct tissue engineering strategies are currently being developed. Cell-based therapies, implantation of synthetic scaffolds or combination of a scaffold with seeded cells are being used according to the biologic premises. Mitochondria play a central role in cell life cycle due to their preponderant role in energy production. Recent data suggest that small non-coding RNAs encoded by mitochondria DNA such as microRNAs regulate a plethora of factors and consequently signaling pathways, crucial in disease pathogenesis and also putatively in regenerative processes. Unveiling mitochondrial microRNAs biological function and their targets will propel the development of innovative therapeutic and diagnostic tools.The most famous role of mitochondria is to generate ATP through oxidative phosphorylation, a metabolic pathway that involves a chain of four protein complexes (the electron transport chain, ETC) that generates a proton-motive force that in turn drives the ATP synthesis by the Complex V (ATP synthase). An impressive number of more than 1000 mitochondrial proteins have been discovered. Since mitochondrial proteins have a dual genetic origin, it is predicted that ~99% of these proteins are nuclear-encoded and are synthesized in the cytoplasmatic compartment, being further imported through mitochondrial membrane transporters. The lasting 1% of mitochondrial proteins are encoded by the mitochondrial genome and synthesized by the mitochondrial ribosome (mitoribosome). As a result, an appropriate regulation of mitochondrial protein synthesis is absolutely required to achieve and maintain normal mitochondrial function. Regarding miRNAs in mitochondria, it is well-recognized nowadays that several cellular mechanisms involving mitochondria are regulated by many genetic players that originate from either nuclear- or mitochondrial-encoded small noncoding RNAs (sncRNAs). Growing evidence collected from whole genome and transcriptome sequencing highlight the role of distinct members of this class, from short interfering RNAs (siRNAs) to miRNAs and long noncoding RNAs (lncRNAs). Some of the mechanisms that have been shown to be modulated are the expression of mitochondrial proteins itself, as well as the more complex coordination of mitochondrial structure and dynamics with its function. We devote particular attention to the role of mitochondrial miRNAs and to their role in the modulation of several molecular processes that could ultimately contribute to tissue regeneration accomplishment.

Subcellular microRNAs in diabetic cardiomyopathy.

Cardiovascular complications are the leading causes of diabetes-related morbidity and mortality. The high incidence and poor prognosis of heart failure in diabetic patients have been associated, in part, to the presence of an underlying cardiomyopathy characterized by cardiac hypertrophy, cardiomyocytes apoptosis, and fibrosis. It has been unclear about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction. Micro(mi)RNAs represent a class of small, 18- to 28-nucleotide-long, non-coding RNA molecules. MiRNAs typically suppress gene expression at the post-transcriptional levels by binding directly to the 3'-UTR of the target mRNAs in the cytoplasm. Interestingly, recent studies suggest that miRNAs may also regulate gene expression in a positive manner. Our recent studies have shown that subcellular miRNAs, such as cytosol-, mitochondria- and nucleus-localized miRNAs, were dramatically dysregulated in diabetic cardiomyopathy. Specifically, cytoplasm localized miRNAs regulate genes expression in a post-transcriptional manner. Nuclear localized miRNAs regulate gene transcription or chromosomal reconstruction through the non-canonical mechanism. Mitochondrial miRNAs stimulate, rather than repress, the translation of specific mitochondrial genome-encoded transcripts. By reviewing these latest discovered functions of subcellular miRNAs in diabetic animal models, we identified new mechanistic insights for diabetic cardiomyopathy. Understanding the nature of subcellular miRNAs will provide new therapeutic targets against diabetes-associated cardiac complications in the near future.