{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman mitochondrial transcription factor B2 (TFB2M) is a pivotal regulator of mitochondrial DNA (mtDNA) transcription. In a reconstituted transcription system, TFB2M partners with the mitochondrial RNA polymerase (POLRMT) and transcription factor A (TFAM) to initiate promoter‐specific transcription by directly interacting with POLRMT. Structural and biochemical studies demonstrate that TFB2M facilitates promoter opening by inducing conformational changes in POLRMT that enable the separation of the DNA strands and the stabilization of the non‐template strand, ensuring precise transcription initiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its essential role in transcription initiation, TFB2M is critical for the maintenance and replication of mtDNA. Experimental elevation of TFB2M leads to increased mtDNA copy number and transcript levels, highlighting distinct functions compared with its paralog TFB1M. TFB2M is intricately involved in coordinating mitochondrial biogenesis and influencing cellular growth via retrograde signaling mechanisms that link mitochondrial performance to nuclear responses. Aberrant expression or mutations in TFB2M have been implicated in a range of conditions—from cardiac hypertrophy and defective mitochondrial translation to neurodegenerative disorders and several cancers (including hepatocellular carcinoma, ovarian cancer, and Parkinson’s disease) as well as autism spectrum disorder—emphasizing its broad impact on mitochondrial function and human pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the mechanistic level, TFB2M’s activity is further fine‐tuned by post‐translational modifications and its interplay with other mitochondrial proteins. Phosphorylation at specific residues has been shown to impair its ability to bind DNA in the promoter region, thereby modulating transcriptional output. In addition, studies using promoter‐independent transcription assays reveal that, while TFB2M is necessary for efficient RNA synthesis on supercoiled DNA templates, the presence of TFAM and mitochondrial single-stranded DNA binding proteins helps suppress spurious transcription events, ensuring fidelity in mtDNA expression. Importantly, loss of TFB2M results in complete depletion of mtDNA, underscoring its indispensable function in both transcription and replication priming."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Maria Falkenberg, Martina Gaspari, Anja Rantanen, et al. 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