Translational Regulation of the Mitochondrial Genome Following Redistribution of
Mitochondrial MicroRNA (MitomiR) in the Diabetic Heart.
Authors Jagannathan R, Thapa D, Nichols CE, Shepherd DL, Stricker JC, Croston TL,
Baseler WA, Lewis SE, Martinez I, Hollander JM
Submitted By John Hollander on 11/9/2015
Status Published
Journal Circulation. Cardiovascular genetics
Year 2015
Date Published 9/1/2015
Volume : Pages Not Specified : Not Specified
PubMed Reference 26377859
Abstract -Cardiomyocytes are rich in mitochondria which are situated in
spatially-distinct subcellular regions including those under the plasma
membrane, subsarcolemmal mitochondria; and those between the myofibrils,
interfibrillar mitochondria. We previously observed subpopulation-specific
differences in mitochondrial proteomes following diabetic insult. The objective
of this study was to determine whether mitochondrial genome-encoded proteins are
regulated by microRNAs inside the mitochondrion and whether subcellular spatial
location or diabetes mellitus influences the dynamics., -Using microarray
technology coupled with cross-linking immunoprecipitation and next generation
sequencing, we identified a pool of mitochondrial microRNAs, termed mitomiRs
that are redistributed in spatially-distinct mitochondrial subpopulations in an
inverse manner following diabetic insult. Redistributed mitomiRs displayed
distinct interactions with the mitochondrial genome requiring specific
stoichiometric associations with RISC constituents argonaute-2 (Ago2) and
fragile X mental retardation-related protein 1 (FXR1) for translational
regulation. In the presence of Ago2 and FXR1, redistribution of mitomiR-378 to
the IFM following diabetic insult led to down regulation of
mitochondrially-encoded F0 component ATP6. Next generation sequencing analyses
identified specific transcriptome and mitomiR sequences associated with ATP6
regulation. Overexpression of mitomiR-378 in HL-1 cells resulted in its
accumulation in the mitochondrion and down-regulation of functional ATP6
protein, while antagomir blockade restored functional ATP6 protein and cardiac
pump function., -We propose mitomiRs can translationally regulate
mitochondrially-encoded proteins in spatially-distinct mitochondrial
subpopulations during diabetes mellitus. The results reveal the requirement of
RISC constituents in the mitochondrion for functional mitomiR translational
regulation and provide a connecting link between diabetic insult and ATP
synthase function.

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