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Nuclear‐mitochondrial crosstalk in the heart during diabetes mellitus – the impact on RNA in mitochondrial subpopulations
Author(s) -
Hathaway Quincy Alexander,
Shepherd Danielle Lee,
Durr Andrya Jean,
Hollander John Michael
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.585.3
Subject(s) - biology , h3k4me3 , epigenetics , mitochondrial dna , mitochondrion , mt rnr1 , diabetic cardiomyopathy , microbiology and biotechnology , genetics , gene , promoter , medicine , gene expression , cardiomyopathy , heart failure
The cellular milieu of diabetes mellitus, with changing substrate utilization, ROS, inflammation, and other factors, influences the function of the mitochondrion, which plays a vital role in bioenergetics. How the mitochondrion functions is affected both by the import of nuclear‐encoded mitochondrial proteins and by regulation of RNA transcripts within the mitochondrion. We have previously shown during diabetes mellitus, that pathways involving protein (HSPA9) and small RNA (PNPase) import are directly impacted. The implications of epigenetic control of the genome, which is shown to be globally altered in the diabetic heart, is relatively unexplored in regards to mitochondrial health and function. Type 2 Diabetic and non‐diabetic human right atrial tissue and db/db mouse whole heart were used for evaluation of epigenetic modifications to nuclear‐encoded mitochondrial proteins involved in protein and RNA import into the mitochondrion, HSPA9 and PNPT1, respectively. Also, analysis of human atrial mitochondrial RNA was examined. The promoter region of HSPA9 and PNPT1 were processed for histone activation/repression (H3K4me3 and H3K27me3, respectively) and DNA methylation. Chromatin‐immunoprecipitation qPCR evaluated differentially bound regions of H3K4me3 and H3K27me3. Bisulfite treatment, methylation PCR, and cloning were used to measure methylation status of CpG islands. Small RNAs were sequenced through NextGen sequencing for mitochondrial subpopulations, subsarcolemmal (SSM) and interfibrillar (IFM). During the diabetic pathology, HSPA9 was shown to have increased H3K27me3 association in human and mouse ( P ≤ 0.05), while PNPT1 exhibited significantly lower H3K27me3 ( P ≤ 0.05) and higher H3K4me3 ( P ≤ 0.05) association in human and mouse. Neither gene had differential methylation patterns during type 2 diabetes mellitus. In type 2 diabetes mellitus, all human mitochondrial transcribed RNA transcripts had a significant decrease in expression in the SSM ( P adj ≤ 0.05), while no changes in the IFM were observed. Our results suggest that during type 2 diabetes mellitus, nuclear‐encoded proteins that comprise the mitochondrial proteome and are involved in protein and RNA import can be epigenetically altered. Mitochondrial subpopulations also differentially express RNA during diabetic insult, with the SSM being more detrimentally impacted. Epigenetic alterations, and changes in RNA, reveal how environmental changes to the nuclear genome could shape mitochondrial structure and function. Support or Funding Information (Support: NIH R01 HL128485; AHA 17PRE33660333) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .