Mitochondrial RNA degradation

Stable Identifier
Homo sapiens
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The human mitochondrial genome encodes two rRNAs, 22 tRNAs, and 13 proteins. The mitochondrial genome is transcribed from two divergent promoters into two large precursor RNAs, one from each strand, that are endonucleolytically processed into individual mRNAs, tRNAs, and rRNAs (Mercer et al. 2011, reviewed in Barchiesi and Vascotto 2019, Jedynak-Slyvka et al. 2021, Rackham and Filipovska 2022). Heavy strand (H-strand) DNA is significantly more G-rich than light strand (L-strand) DNA. Transcripts from the H-strand encode eight monocistronic mRNAs, two bicistronic mRNAs (MT-ATP8/6 and MT-ND4L/4), 14 tRNAs, and two rRNAs. Transcripts from the L‑strand encode only one mRNA (MT‑ND6), one long non-coding RNA (lncRNA), lncND6, which is antisense to MT-ND6, and eight tRNAs, and two long non-coding RNAs designated as lncND5, and lncCyt b RNA that are antisense to the coding mRNAs MT-ND5 and MT-CYB (CYTB, MT-Cytb) (Rackham et al. 2011). The L-strand and H-strand transcripts are complementary and, therefore, have the potential to form large double-stranded RNAs (dsRNAs), yet very little dsRNA is observed in wild-type mitochondria.
Both dsRNAs and normal mRNAs, tRNAs, and rRNAs are hydrolyzed by the SUPV3L1:PNPT1 complex, called the degradosome, which is located mostly in mitochondrial RNA granules (MRGs) adjacent to the DNA-containing nucleoid (reviewed in Borowski et al. 2010, Rorbach and Minczuk 2012, Kotrys and Szczesny 2019, Rackham and Filipovska 2022). Degradation appears to occur in subregions of MRGs called D-foci (Borowski et al. 2013, Van Haute et al. 2015). SUPV3L1 is a helicase that unwinds double-stranded RNA (Shu et al. 2004, Wang et al. 2009, Dhir et al. 2018, Jain et al. 2022) to provide single-stranded substrate to the PNPT1 exonuclease (Wang et al. 2009, Lin et al. 2012). Additionally, G quadruplex structures in a subset of RNAs are unwound by GRSF1 to provide substrates to the SUPV3L1:PNPT1 complex (Antonicka et al. 2013, Pietras et al. 2018). However, other RNAs are stabilized by GRSF1 (Antonicka et al. 2013). The PNPT1 3'-5' exonuclease hydrolyzes RNAs to yield 4-5 nucleotide "nanoRNAs" which are further hydrolyzed to mononucleotides by the REXO2 dimer (Bruni et al. 2013, Szewczyk et al. 2020).
Degradation of mitochondrial RNAs is regulated by RNA-binding proteins: FASTK, FASTKD1-5, and the SLIRP:LRPPRC complex (Sasarman et al. 2010, Chujo et al. 2021, Ruzzenente et al. 2012, Jourdain et al. 2017, Siira et al. 2017, reviewed in Rackham and Filipovska 2022). SLIRP:LRPPRC binds throughout the mitochondrial transcriptome, including 12S rRNA, 16S rRNA, and 13 mRNAs, and acts to stabilize RNA structures, inhibit hybridization of complementary RNAs, and extend the half-lives of RNAs (Sasarman et al. 2010, Chujo et al. 2012, Siira et al. 2017). Fas-activated serine/threonine kinase (FASTK) and its homologs FASTKD1-5 bind particular mitochondrial RNAs and affect their stability and processing (reviewed in Jourdain et al. 2017, Rackham and Filipovska 2022).
Literature References
PubMed ID Title Journal Year
22642575 The post-transcriptional life of mammalian mitochondrial RNA

Minczuk, M, Rorbach, J

Biochem. J. 2012
30525095 Controlling the mitochondrial antisense - role of the SUV3-PNPase complex and its co-factor GRSF1 in mitochondrial RNA surveillance

Dziembowski, A, Stepien, PP, Szczesny, RJ, Szewczyk, M, Wojcik, MA, Kulinski, TM, Borowski, LS, Cysewski, D, Pietras, Z

Mol Cell Oncol 2018
34360765 Human Mitochondrial RNA Processing and Modifications: Overview

Jabczynska, A, Jedynak-Slyvka, M, Szczesny, RJ

Int J Mol Sci 2021
20117077 RNA turnover in human mitochondria: more questions than answers?

Brzezniak, LK, Stepien, PP, Szczesny, RJ, Borowski, LS

Biochim Biophys Acta 2010
29146908 LRPPRC-mediated folding of the mitochondrial transcriptome

Shearwood, AJ, Ruzzenente, B, Filipovska, A, Larsson, NG, Spåhr, H, Siira, SJ, Rackham, O

Nat Commun 2017
15096047 Purified human SUV3p exhibits multiple-substrate unwinding activity upon conformational change

Chen, PL, Shu, Z, Vijayakumar, S, Lee, WH, Chen, CF

Biochemistry 2004
26016801 Mitochondrial transcript maturation and its disorders

Powell, CA, Minczuk, M, Van Haute, L, Nicholls, TJ, Pearce, SF, D'Souza, AR

J. Inherit. Metab. Dis. 2015
22045337 LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs

Park, CB, Bratic, A, Ruzzenente, B, Larsson, NG, Stewart, JB, Brandt, U, Gustafsson, CM, Tempst, P, Erdjument-Bromage, H, Cámara, Y, Milenkovic, D, Hultenby, K, Metodiev, MD, Wredenberg, A, Wibom, R, Zickermann, V

EMBO J 2012
29036396 The FASTK family of proteins: emerging regulators of mitochondrial RNA biology

Anderson, P, Simarro, M, de la Fuente, MA, Martinou, JC, Popow, J, Jourdain, AA

Nucleic Acids Res 2017
19509288 Human mitochondrial SUV3 and polynucleotide phosphorylase form a 330-kDa heteropentamer to cooperatively degrade double-stranded RNA with a 3'-to-5' directionality

Wang, DD, Chen, PL, Shu, Z, Lieser, SA, Lee, WH

J Biol Chem 2009
22028365 Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins

Mattick, JS, Mercer, TR, Filipovska, A, Shearwood, AM, Davies, SM, Rackham, O

RNA 2011
31064115 Transcription, Processing, and Decay of Mitochondrial RNA in Health and Disease

Barchiesi, A, Vascotto, C

Int J Mol Sci 2019
32365187 Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent accumulation of double-stranded RNA

Kotrys, AV, Nowotny, M, Malik, D, Szczesny, RJ, Szewczyk, M, Czarnomska, SD, Borowski, LS, Klosowska-Kosicka, K

Nucleic Acids Res 2020
29967381 Dedicated surveillance mechanism controls G-quadruplex forming non-coding RNAs in human mitochondria

Dziembowski, A, Stepien, PP, Szczesny, RJ, Szewczyk, M, Wojcik, MA, Kulinski, TM, Borowski, LS, Cysewski, D, Pietras, Z

Nat Commun 2018
20200222 LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria

Antonicka, H, Consortium, LSFC, Sasarman, F, Shoubridge, EA, Wai, T, Brunel-Guitton, C

Mol Biol Cell 2010
31861673 Mitochondrial Gene Expression and Beyond-Novel Aspects of Cellular Physiology

Kotrys, AV, Szczesny, RJ

Cells 2019
35459860 Organization and expression of the mammalian mitochondrial genome

Filipovska, A, Rackham, O

Nat Rev Genet 2022
23741365 REXO2 is an oligoribonuclease active in human mitochondria

Lightowlers, RN, Chrzanowska-Lightowlers, ZM, Oliveira, JM, Gramegna, P, Bruni, F

PLoS One 2013
21854988 The human mitochondrial transcriptome

Mattick, JS, Haugen, E, Crawford, J, Neph, S, Mercer, TR, Filipovska, A, Shearwood, AM, Bracken, CP, Rackham, O, Dinger, ME, Stamatoyannopoulos, JA, Smith, MA

Cell 2011
22210891 Crystal structure of human polynucleotide phosphorylase: insights into its domain function in RNA binding and degradation

Yang, WZ, Hsiao, YY, Lin, CL, Yuan, HS, Wang, YT

Nucleic Acids Res 2012
23473033 The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required for posttranscriptional mitochondrial gene expression

Paupe, V, Antonicka, H, Sasarman, F, Shoubridge, EA, Nishimura, T

Cell Metab 2013
22661577 LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promotes polyadenylation in human mitochondria

Suzuki, T, Chujo, T, Ohira, T, Nomura, N, Sakaguchi, Y, Nagao, A, Goshima, N

Nucleic Acids Res 2012
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