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J Mol Cell Cardiol. 2017 Sep;110:15-25. doi: 10.1016/j.yjmcc.2017.06.012. Epub 2017 Jul 11.

Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase).

Author information

1
Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV 26506, United States; Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV 26506, United States.
2
Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV 26506, United States.
3
Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV 26506, United States.
4
Cancer Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506, United States.
5
Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV 26506, United States; Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV 26506, United States. Electronic address: jhollander@hsc.wvu.edu.

Abstract

Cardiovascular disease is the primary cause of mortality for individuals with type 2 diabetes mellitus. During the diabetic condition, cardiovascular dysfunction can be partially attributed to molecular changes in the tissue, including alterations in microRNA (miRNA) interactions. MiRNAs have been reported in the mitochondrion and their presence may influence cellular bioenergetics, creating decrements in functional capacity. In this study, we examined the roles of Argonaute 2 (Ago2), a protein associated with cytosolic and mitochondrial miRNAs, and Polynucleotide Phosphorylase (PNPase), a protein found in the inner membrane space of the mitochondrion, to determine their role in mitochondrial miRNA import. In cardiac tissue from human and mouse models of type 2 diabetes mellitus, Ago2 protein levels were unchanged while PNPase protein expression levels were increased; also, there was an increase in the association between both proteins in the diabetic state. MiRNA-378 was found to be significantly increased in db/db mice, leading to decrements in ATP6 levels and ATP synthase activity, which was also exhibited when overexpressing PNPase in HL-1 cardiomyocytes and in HL-1 cells with stable miRNA-378 overexpression (HL-1-378). To assess potential therapeutic interventions, flow cytometry evaluated the capacity for targeting miRNA-378 species in mitochondria through antimiR treatment, revealing miRNA-378 level-dependent inhibition. Our study establishes PNPase as a contributor to mitochondrial miRNA import through the transport of miRNA-378, which may regulate bioenergetics during type 2 diabetes mellitus. Further, our data provide evidence that manipulation of PNPase levels may enhance the delivery of antimiR therapeutics to mitochondria in physiological and pathological conditions.

KEYWORDS:

Bioenergetics; Diabetes mellitus; Mitochondria; microRNA

PMID:
28709769
PMCID:
PMC5854179
DOI:
10.1016/j.yjmcc.2017.06.012
[Indexed for MEDLINE]
Free PMC Article

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