Abstract
Mitochondria are essential molecular machinery for the maintenance of cellular energy supply by the oxidative phosphorylation system (OXPHOS). Mitochondrial transcription factor B1 (TFB1M) is a dimethyltransferase that maintains mitochondrial homeostasis by catalyzing dimethylation of two adjacent adenines located in helix45 (h45) of 12S rRNA. This m62A modification is indispensable for the assembly and maturation of human mitochondrial ribosomes. However, both the mechanism of TFB1M catalysis and the precise function of TFB1M in mitochondrial homeostasis are unknown. Here we report the crystal structures of a ternary complex of human (hs) TFB1M–h45–S-adenosyl-methionine and a binary complex hsTFB1M–h45. The structures revealed a distinct mode of hsTFB1M interaction with its rRNA substrate and with the initial enzymatic state involved in m62A modification. The suppression of hsTFB1M protein level or the overexpression of inactive hsTFB1M mutants resulted in decreased ATP production and reduced expression of components of the mitochondrial OXPHOS without affecting transcription of the corresponding genes and their localization to the mitochondria. Therefore, hsTFB1M regulated the translation of mitochondrial genes rather than their transcription via m62A modification in h45.
Highlights
As a unique organelle in eukaryotes, mitochondria have retained a unique double-stranded circular DNA genome
The mtDNA genome encodes 22 transfer RNAs, two ribosomal RNAs, and 13 protein components of the oxidative phosphorylation system (OXPHOS), which produces the majority of cellular ATP [1,2,3]
HsTFB1M shares a common fold with ribosomal RNAs (rRNAs) adenine methyltransferases
Summary
As a unique organelle in eukaryotes, mitochondria have retained a unique double-stranded circular DNA genome (mtDNA). The mtDNA genome encodes 22 transfer RNAs (tRNAs), two ribosomal RNAs (rRNAs), and 13 protein components of the oxidative phosphorylation system (OXPHOS), which produces the majority of cellular ATP [1,2,3]. The expression of a substantial number of proteins and nucleic acids are coordinated by the mtDNA and nuclear genome to partake in respiration. OXPHOS complexes comprise 13 mtDNA-encoded subunits and 70 nuclear genome-encoded subunits that assemble to form four of the five enzymatic complexes essential for ATP production [4]. Mitochondria play a vital role in eukaryotic energy conversion and metabolism. A growing number of diseases are considered to be inseparably linked to mitochondrial dysfunction, including age-related chronic diseases, inherited diseases and cancers [5,6]
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