Journal
MITOCHONDRION
Volume 61, Issue -, Pages 11-24Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.mito.2021.09.001
Keywords
Mild traumatic brain injury; Mitochondrial biogenesis; Mitochondrial transcription factor A; DNA methylation; Heavy strand promoter; mitochondrial DNA
Categories
Funding
- University Grants Commission, Government of India (UGC, GOI) [F.4-5/151-FRP/2014/BSR]
- Science and Engineering Research Board (SERB, GOI) [EMR/2017/000621]
- Council for Scientific and Industrial Research (CSIR, GOI) [37[1718]/18/EMR-II]
- Rashtriya Uchchatar Shiksha Abhiyan, Savitribai Phule Pune University (RUSA, GOI)
- UGC, GOI [2061330923, 805/CSIR-UGC NET JUNE 2018]
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The study found that repeated mild traumatic brain injury (rMTBI) results in hypermethylation at the TFAM promoter and hypomethylation at mitochondrial DNA (mtDNA) promoters (HSP1 and HSP2), leading to impaired mitochondrial biogenesis and reduced ATP levels in the hippocampus. Treatment with methionine, a methyl donor, restored methylation levels on mtDNA promoters and normalized mitochondrial gene expression and ATP activity.
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 hippo campus 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.
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