https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.molonc.2012.09.006

MicroRNA and cancer.

Oxidative stress and mitochondrial dysfunction in Alzheimer's disease

Mitochondrial morphology varies tremendously across cell types and tissues, changing rapidly in response to external insults and metabolic cues, such as nutrient status. The many functions of mitochondria have been intimately linked to their morphology, which is shaped by ongoing events of fusion and fission of outer and inner membranes (OM and IM). Unopposed fission causes mitochondrial fragmentation, which is generally associated with metabolic dysfunction and disease. Unopposed fusion results in a hyperfused network and serves to counteract metabolic insults, preserve cellular integrity, and protect against autophagy. Here, we review the ways in which metabolic alterations convey changes in mitochondrial morphology and how disruption of mitochondrial morphology impacts cellular and organismal metabolism.

Mitochondrial Dynamics and Metabolic Regulation.

MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

http://www.jbc.org/content/279/34/36166.1.full.pdf

hFis1, a novel component of the mammalian mitochondrial fission machinery. Vol. 278 (2003) 36373–36379

miRNAs participate in the regulation of apoptosis. However, it remains largely unknown as to how miRNAs are integrated into the apoptotic program. Mitochondrial fission is involved in the initiation of apoptosis. It is not yet clear whether miRNAs are able to regulate mitochondrial fission. Here we report that miR-30 family members are able to regulate apoptosis by targeting the mitochondrial fission machinery. Our data show that miR-30 family members can inhibit mitochondrial fission and the consequent apoptosis. In exploring the underlying molecular mechanism, we identified that miR-30 family members can suppress p53 expression. In response to the apoptotic stimulation, the expression levels of miR-30 family members were reduced, whereas p53 was upregulated. p53 transcriptionally activated the mitochondrial fission protein, dynamin-related protein-1 (Drp1). The latter conveyed the apoptotic signal of p53 by initiating the mitochondrial fission program. miR-30 family members inhibited mitochondrial fission through suppressing the expression of p53 and its downstream target Drp1. Our data reveal a novel model in which a miRNA can regulate apoptosis through targeting the mitochondrial fission machinery.

miR-30 Regulates Mitochondrial Fission through Targeting p53 and the Dynamin-Related Protein-1 Pathway

Mitochondria supply energy for physiological function and they participate in the regulation of other cellular events including apoptosis, calcium homeostasis, and production of reactive oxygen species. Thus, mitochondria play a critical role in the cells. However, dysfunction of mitochondria is related to a variety of pathological processes and diseases. MicroRNAs (miRNAs) are a class of small noncoding RNAs about 22 nucleotides long, and they can bind to the 3′-untranslated region (3′-UTR) of mRNAs, thereby inhibiting mRNA translation or promoting mRNA degradation. We summarize the molecular regulation of mitochondrial metabolism, structure, and function by miRNAs. Modulation of miRNAs levels may provide a new therapeutic approach for the treatment of mitochondria-related diseases. J. Cell. Biochem. 113: 1104–1110, 2012. © 2011 Wiley Periodicals, Inc.

Control of mitochondrial activity by miRNAs

MicroRNAs (miRNAs) are a class of small noncoding RNAs that mediate posttranscriptional gene silencing Mitochondrial fission participates in the induction of apoptosis It remains largely unknown whether miRNAs can regulate mitochondrial fission Reactive oxygen species and doxorubicin could induce mitochondrial fission and apoptosis in cardiomyocytes Concomitantly, mitofusin 1 (Mfn1) was downregulated, whereas miRNA 140 (miR-140) was upregulated upon apoptotic stimulation We investigated whether Mfn1 and miR-140 play a functional role in mitochondrial fission and apoptosis Ectopic expression of Mfn1 attenuated mitochondrial fission and apoptosis Knockdown of miR-140 inhibited mitochondrial fission Our results further revealed that knockdown of miR-140 was able to reduce myocardial infarct sizes in an animal model We observed that miR-140 could suppress the expression of Mfn1, and it exerted its effect on mitochondrial fission and apoptosis through targeting Mfn1 Our data revealed that mitochondrial fission occurs in cardiomyocytes and can be counteracted by Mfn1 However, the function of Mfn1 is negatively regulated by miR-140 Our present work suggests that Mfn1 and miR-140 are integrated into the program of cardiomyocyte apoptosis

Mitofusin 1 is negatively regulated by microRNA 140 in cardiomyocyte apoptosis.

miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor

Despite its complexity of action, doxorubicin (Dox)-induced cardiomyopathy eventually results in loss of cardiac myocytes which further contributes to the development of overt heart failure. In the present study, we examined the relevance of the apoptosis repressor with caspase recruitment domain (ARC) on cardiac myocyte survival and its underlying mechanisms in a model of Dox-induced cardiotoxicity. Exposure of neonatal rat ventricular cardiomyocytes with Dox resulted in a downregulation of ARC mRNA and protein levels that occurred in a pre-translational and post-translational manner and led to a significant induction of apoptosis. Proteasomal inhibitors partially rescued both Dox-induced downregulation of ARC protein and induction of apoptosis. Knockdown of endogenous ARC sensitised cardiomyocytes to undergo apoptosis upon treatment with Dox. In contrast, enforced expression of ARC by adenoviral-mediated gene transfer dramatically increased the resistance of cardiomyocytes to undergo apoptotic cell death following Dox administration. In response to Dox, Bax translocated from cytosol to mitochondria where it resulted in dissipation of the mitochondrial membrane potential, cytochrome c release and activation of caspases -3 and -9. ARC prevented Bax translocation to the mitochondrium and thereby blocked the activation of the mitochondrial apoptotic death pathway in a t-Bid and caspase-8-independent manner. In this study, we provide evidence for the protective role of anti-apoptotic ARC in Dox-induced cardiotoxicity, which makes this molecule an interesting target for future therapies.

Peifeng Li

Papers

miR-30 Regulates Mitochondrial Fission through Targeting p53 and the Dynamin-Related Protein-1 Pathway

Control of mitochondrial activity by miRNAs

Mitofusin 1 is negatively regulated by microRNA 140 in cardiomyocyte apoptosis.

miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor

ARC is a critical cardiomyocyte survival switch in doxorubicin cardiotoxicity