Abstract Body (Do not enter title and authors here): BACKGROUND: Mitochondria are highly-responsive organelles with diverse functions. Mitochondrial transcription factor A (TFAM) serves as a pivotal regulator of mitochondrial biogenesis by directly inducing the replication and transcription of mitochondrial genome. Tfam disruption in mice causes cardiac dysfunction. In this study, we examined its role in maintaining mitochondrial integrity in aortic smooth muscle cells and protecting aortas from sporadic aortic aneurysm and dissection (AAD).
METHODS: In angiotensin II (Ang II)-infused AAD mouse model, the transcriptomic and epigenomic dynamics of genes in mitochondrial functions in aortic SMCs were examined by using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq). The role of TFAM in SMC injury and AAD development was determined in SMC-specific Tfam deletion (SMC-Tfam-/-) mice.
RESULTS: ScRNA-seq analysis of aortas in Ang II-induced WT mice revealed a paradigm wherein aortic distress caused transcriptional downregulation of mitochondrial-encoded genes and an upsurge in the expression of nuclear-encoded mitochondrial counterparts in SMCs. Remarkably, SMC-Tfam^-/- mice exhibited a substantial suppression of nuclear-encoded mitochondrial genes, with only negligible alterations in mitochondrial genes. ScATAC-seq illuminated that the upregulation of nuclear-encoded mitochondrial genes in SMCs in WT mice was modulated, in part, at the epigenetic level through enhanced chromatin accessibility. However, induction of open chromatin states of mitochondrial genes was compromised in SMC-Tfam^-/- mice. Finally, SMC-Tfam^-/- mice manifested a pronounced susceptibility to AngII-induced SMC inflammatory response and death, aortic dissection and rupture in both thoracic and abdominal aortas.
CONCLUSION: Our study suggests that TFAM plays a pivotal role in epigenetic induction of nuclear-encoded mitochondrial genes. These findings not only improve our comprehension of TFAM's regulatory spectrum but also underscore the importance of the nuclear - mitochondrial interaction in maintaining mitochondrial homeostasis.