Identifying a novel Mecp2-mediated epigenetic mechanism controlling Lonp1 in the hippocampus and its disruption by aging

Aging is characterized by a progressive decline in cellular function, including the hippocampus, a brain region crucial for learning and memory. Mitochondrial dysfunction is a hallmark of aging, critical for hippocampal deterioration. The mitochondrial protease Lonp1 is a key regulator of mitochondrial proteostasis, and its diminished expression or activity has been implicated in age-related dysfunction in non-neuronal cells. However, despite its essential role in maintaining mitochondrial function, the transcriptional regulation of Lonp1 remains poorly understood. Evidence suggests that Lonp1 is subject to epigenetic control via changes in DNA methylation patterns. Mepc2, a DNA-methylation reader, acts as a transcriptional regulator highly expressed in neurons, either activating or repressing gene expression. Yet, its role in the mitochondria of aged hippocampus and its potential role as Lonp1 regulator haven’t been explored. Here, we investigated Lonp1 expression and its epigenetic regulation by Mecp2 in the hippocampus of aged SAMP8 mice. We identified CpG islands in the Lonp1 promoter, near the transcription start site, where DNA methylation levels increase in aged hippocampal tissue. Chromatin immunoprecipitation revealed that Mecp2 directly binds to the Lonp1 promoter, with a significant reduction in binding observed in aged mice, correlating with increased Lonp1 mRNA levels. These findings show, for the first time, that Mecp2 is a transcriptional repressor of Lonp1 in the hippocampus. Additionally, unlike humans expressing three isoforms of Lonp1, mice exhibit only the full-length mitochondrial isoform. Interestingly, despite increased Lonp1 mRNA levels in aged mice, their protein levels were significantly decreased in the aged hippocampus. This unexpected result is, at least in part, explained by the enhanced Lonp1 protein degradation by the lysosome. Together, our findings reveal a novel mechanism that drives Lonp1 expression, linking Mecp2-mediated epigenetic regulation to age-related mitochondrial dysfunction. This study reveals Mecp2 and Lonp1 as potential therapeutic targets for mitochondrial proteostasis in aging.