Martin Hällberg

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Structural Biochemistry in Mitochondrial RNA Biogenesis

"I see the CSSB as an opportunity to participate in a truly exciting multidisciplinary approach to molecular biology. The location at the DESY campus is a unique opportunity with a range of world-class facilities, such as PETRA III and the future European X-FEL."

Martin Hällberg, CSSB Group Leader

Previous and current research

Mitochondrial RNA Biogenesis

We work with the biochemistry and structural biology of RNA biogenesis. Given that impaired gene expression of mitochondrial DNA can lead to mitochondrial disease and pre-mature aging, the current focus of our group is to study mitochondrial gene expression.

Understanding Mitochondrial RNA Processing
Transcription in human mitochondria gives rise to long polycistronic transcripts that need to be extensively processed in order to obtain mature RNA units that can be used in translation, the synthesis of proteins within the mitochondrion. A multitude of recent work shows that mitochondrial RNase P (mt-RNase P) initiates this processing by cleaving the polycistronic transcripts in the 5-ends of mitochondrial tRNA genes. Mammalian mt-RNase P is a tripartite protein complex that consists of MRPP1, MRPP2 and MRPP3. In Reinhard et al., 2015, we determined the structure of the nuclease subunit of the human mitochondrial RNase P (MRPP3) and showed that is has a non-functional active site in isolation. However, the nuclease subunit is capable of reforming a normal active site once its partners MRPP1 and MRPP2 are bound together with tRNA in an induced fit process. This work revealed the molecular basis for regulation of one of the key enzymes of human mitochondrial gene expression.

Polyadenylation of mRNA
Polyadenylation alters the fate of mRNAs in several ways. It can increase mRNA stability, stimulate translation initiation, promote degradation or be required for completing certain stop codons that are not encoded in mtDNA. Polyadenylation is critical for mitochondrial translation and hence energy generation by the mitochondrion.” In Lapkouski & Hällberg 2015, we determined the first high-resolution structure of a vertebrate mitochondrial poly-A polymerase which adds polyadenines to the 3’-ends of mitochondrial mRNAs. Through high-resolution co-substrate ternary complexes, we could propose a structure-based hypothesis for why and how a mutation that causes spastic ataxia, a rare neurodegenerative disorder affecting balance, speech, movement of the arms, legs, and tongue, results in strongly reduced mRNA polyadenylation.

After processing, mitochondrial tRNAs and rRNAs need to be chemically modified. In Spåhr et al. 2012, we determined the crystal structure of the MTERF4-NSUN4 complex that methylates the mitochondrial small subunit rRNA and is critical for mammalian mitoribosome biogenesis. Based on the structure we proposed that MTERF4 act as a molecular ruler and helps orient NSUN4 for catalysis on the mitoribosome.

Future goals
We will continue the work in mitochondrial RNA biogenesis focussing on reconsituting larger processing complexes combined with biochemical work to understand the the initial RNA processing order in mammalian mitochondria. Furthermore, we will study what happens with the mitochondrial mRNAs after polyadenylation. This research will not only increase our fundamental understanding of the human cellular energy generation but will also open up new avenues for early diagnosis and intervention.

Selected publications
Lapkouski, M., Hällberg, B.M. (2015) Structure of mitochondrial poly(A) RNA polymerase reveals the structural basis for dimerization, ATP selectivity and the SPAX4 disease phenotype. Nucleic Acids Res. 43, 9065-9075

Reinhard, L., Sridhara, S. Hällberg, B.M. (2015) Structure of the nuclease subunit of human mitochondrial RNase P. Nucleic Acids Res. 43, 5664-5672

Posse, V., Shahzad, S., Falkenberg, M., Hällberg, B.M., Gustafsson, C.M. (2015) TEFM is a potent stimulator of mitochondrial transcription elongation in vitro. Nucleic Acids Res. 43, 2615-2624

Posse, V., et al. (2014) The amino terminal extension of mammalian mitochondrial RNA polymerase ensures promoter specific transcription initiation. Nucleic Acids Res. 42, 3638-3647

Spåhr, H., Habermann, B., Gustafsson, C.M., Larsson, N.G., Hallberg, B.M. (2012) Structure of the MTERF4-NSUN4 complex that regulates mitochondrial ribosome biogenesis PNAS 109, 15253-15258