Mitochondrial proteome disruption in the diabetic heart through targeted epigenetic regulation at the mitochondrial heat shock protein 70 (mtHsp70) nuclear locus. (June 2018)

• Record Type: Journal Article
• Authors: Shepherd, Danielle L.; Hathaway, Quincy A.; Nichols, Cody E.; Durr, Andrya J.; Pinti, Mark V.; Hughes, Kristen M.; Kunovac, Amina; Stine, Seth M.; Hollander, John M.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 119(2018)
• Page Start: 104
• Page End: 115
• Publication Date: 2018-06
• Subjects: Diabetes mellitus -- Mitochondria -- Cardioprotection -- Mitochondrial heat shock protein 70 -- Mitochondrial protein import -- Proteomics -- Epigenetics -- Type 2 diabetes mellitus; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.04.016
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: >99% of the mitochondrial proteome is nuclear-encoded. The mitochondrion relies on a coordinated multi-complex process for nuclear genome-encoded mitochondrial protein import. Mitochondrial heat shock protein 70 (mtHsp70) is a key component of this process and a central constituent of the protein import motor. Type 2 diabetes mellitus (T2DM) disrupts mitochondrial proteomic signature which is associated with decreased protein import efficiency. The goal of this study was to manipulate the mitochondrial protein import process through targeted restoration of mtHsp70, in an effort to restore proteomic signature and mitochondrial function in the T2DM heart. A novel line of cardiac-specific mtHsp70 transgenic mice on the db / db background were generated and cardiac mitochondrial subpopulations were isolated with proteomic evaluation and mitochondrial function assessed. MicroRNA and epigenetic regulation of the mtHsp70 gene during T2DM were also evaluated. MtHsp70 overexpression restored cardiac function and nuclear-encoded mitochondrial protein import, contributing to a beneficial impact on proteome signature and enhanced mitochondrial function during T2DM. Further, transcriptional repression at the mtHsp70 genomic locus through increased localization of H3K27me3 during T2DM insult was observed. Our results suggest that restoration of a key protein import constituent, mtHsp70, provides therapeutic benefit through attenuation of mitochondrial and contractile dysfunction in T2DM. Graphical abstract: Unlabelled Image Highlights: Type 2 diabetes mellitus is associated with mitochondrial proteome dysregulation. Type 2 diabetes mellitus decreases mitochondrial protein import via loss of mtHsp70. Loss of mtHsp70 occurs through epigenetic dysregulation at its nuclear locus.