Journal article
Repeated mild traumatic brain injuries perturb the mitochondrial biogenesis via DNA methylation in the hippocampus of rat
Mitochondrion, Vol.61, pp.11-24
11/2021
DOI: 10.1016/j.mito.2021.09.001
Abstract
•Repeated mild traumatic brain injuries (rMTBI) decreased TFAM levels.•rMTBI-induced nuclear DNA hypermethylation declined TFAM levels.•Mitochondrial DNA (mtDNA) hypomethylation after rMTBI attenuated TFAM binding.•Low TFAM occupancy on hypomethylated mtDNA altered mitochondrial biogenesis.•Methionine treatment restored rMTBI-induced mitochondrial biogenesis via mtDNA methylation.
Mitochondrial biogenesis in the brain is impaired in various neurological disorders including traumatic brain injury (TBI). The long-lasting effects of TBI may be, in part, attributed to epigenetic mechanisms such as DNA methylation. However, the role of DNA methylation on regulatory elements of nuclear and mitochondrial genome in mitochondrial biogenesis is not known. We examined the epigenetic regulation of mitochondrial transcription factor A (TFAM), and further probed its implications in mitochondrial dysfunction in the hippocampus of rats subjected to repeated mild TBI (rMTBI) using weight drop injury paradigm. rMTBI-induced hypermethylation at TFAM promoter resulted in deficits in its protein levels in mitochondria after immediate (48 h) and protracted (30 d) time points. Further, rMTBI also caused hypomethylation of mitochondrial DNA (mtDNA) promoters (HSP1 and HSP2), which further culminated into low binding of TFAM. rMTBI-induced changes weakened mitochondrial biogenesis in terms of reduced mtDNA-encoded rRNA, mRNA, and protein levels leading to shortages of ATP. To verify the potential role of mtDNA methylation in rMTBI-induced persistent mitochondrial dysfunction, rMTBI-induced rats were treated with methionine, a methyl donor. Methionine treatment restored the methylation levels on HSP1 and HSP2 resulting in efficient binding of TFAM and normalized the rRNA, mRNA, and protein levels. These findings suggest the crucial role of DNA methylation at nuclear and mitochondrial promoter regions in mitochondrial gene expression and ATP activity in the hippocampus after rMTBI.
Details
- Title: Subtitle
- Repeated mild traumatic brain injuries perturb the mitochondrial biogenesis via DNA methylation in the hippocampus of rat
- Creators
- Nagalakshmi Balasubramanian - University of Iowa, Neuroscience and PharmacologyGouri JadhavAmul J Sakharkar
- Resource Type
- Journal article
- Publication Details
- Mitochondrion, Vol.61, pp.11-24
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.mito.2021.09.001
- ISSN
- 1567-7249
- eISSN
- 1872-8278
- Grant note
- DOI: 10.13039/501100001412, name: Council of Scientific & Industrial Research; DOI: 10.13039/501100001501, name: University Grants Commission; DOI: 10.13039/501100001843, name: Science and Engineering Research Board
- Language
- English
- Date published
- 11/2021
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9984131868702771
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